Contemporary, population-based, cause-specific mortality risks within the heterogeneous subtypes of classical myeloproliferative neoplasms (MPNs)–polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF)–in the United States are needed to inform patient care. Therefore, we leveraged MPN cases diagnosed in the surveillance, epidemiology, and end results (SEER) Program in the 21st century to quantify cause-specific mortality risks and associated burden of death separately for PV, ET, and PMF, overall and by age and sex.

We included all cases of first primary PV, ET, and PMF diagnosed during 2001–2016 (follow-up through 2017) among adult (ages 20–84 years) residents of 17 SEER cancer registry areas. Relative risk of death was estimated using standardized mortality ratios (SMRs; observed/expected), calculated by MPN subtype and stratified by age at diagnosis and sex. Differences in SMRs between subgroups were tested for significance using Poisson regression modeling and likelihood methods. We also calculated excess absolute risks (EAR) per 10 000 person-years and estimated MPN subtype-specific cumulative mortality. See the Methods section in Supporting Information for further details describing the SEER Program, study population, disease groupings, and statistical methods.

We identified 13 340 individuals with PV, 12 346 individuals with ET, and 3230 individuals with PMF (Table 1). Mean follow-up time was 6.5, 6.0, and 4.0 years after a diagnosis of PV, ET, and PMF, respectively. MPNs accounted for < 10% of cause-specific death following a diagnosis of PV and ET and 34% following PMF (Table S1).

All-cause mortality for each MPN exceeded that in the similarly aged general population, with 10-year cumulative mortality reaching 18.3%, 12.5%, and 48.5% for PV, ET, and PMF, respectively, for individuals < 60 years (general population: 6.8%) and 46.7%, 44.7%, and 83.7%, respectively, for those ≥ 60 years (general population: 29.1%) (Figure S1, Table S2). For patients with PV or ET, cumulative mortality for noncancer deaths far exceeded that for cancer deaths throughout 10 years of follow-up. In contrast, for PMF, cumulative incidence of deaths from all noncancers, all hematologic neoplasms (excluding MPN), and MPN were generally similarly elevated, whereas deaths from all solid tumors remained low throughout the follow-up period.

Patients with PV had a 90% increased risk of death from all causes (excluding MPN), when compared to that expected in the general population (SMR = 1.9, 95% CI 1.8–2.0, EAR = 172.1; Table 1). Nearly 75% of these deaths (n = 2279; SMR = 2.0, EAR = 131.1) were due to noncancer causes, with 1.8–2.7-fold significantly increased SMRs observed for infections, including septicemia and respiratory infections; digestive diseases, including liver disease; cerebrovascular disease; cardiovascular diseases, including heart disease; and respiratory diseases, including chronic obstructive pulmonary disease (COPD); and a 4.3-fold elevated risk for benign hematologic disorders. The greatest burden of noncancer excess deaths/10 000 person-years was due to heart disease (EAR = 42.7), with lesser contributions from COPD, cerebrovascular disease, and infections (EARs = 11–21). Most of the relative and excess risks of deaths from neoplasms were accounted for by MDS/AML (SMR = 12.9, EAR = 17.6).

In age and sex-specific analyses for PV, relative risks for all causes (excluding MPN) of death were higher among younger (SMR_<60 = 2.8) compared with older individuals (SMR_≥60 = 1.7, p < .001), but older patients experienced a disproportionate number of excess deaths (EAR_<60 = 126.3 vs. EAR_≥60 = 221.8; Table S3). Significantly higher SMRs due to cerebrovascular disease, heart disease, and COPD occurred among those diagnosed at ages < 60 versus ≥ 60 years, and significantly higher SMRs from heart disease, COPD, adverse events, and MDS/AML were observed among females than males. Heart disease had the highest EAR of non-MPN deaths regardless of age (EAR_<60 = 36.0; EAR_≥60 = 50.1) and sex (EAR_males = 41.9; EAR_females = 44.2).

Significantly increased risks of non-MPN deaths also were seen following a diagnosis of ET (SMR = 1.8, 95% CI = 1.8–1.9, EAR = 149.1). SMRs for noncancer causes were generally similar to PV but smaller in magnitude for most outcomes, with SMRs ranging from 1.7 to 2.2 for infections, digestive diseases, cerebrovascular disease, heart disease, COPD, nephritis/nephrosis, and adverse events. However, notably higher risk for death from benign hematologic disorders was observed (SMR_ET = 12.5; p_{PV vs ET} < .001) and lower risk from COPD (SMR_ET = 1.8; p_{PV vs ET} < .001) for ET compared with PV. Deaths due to solid cancers were not elevated beyond expectation after ET (SMR = 1.0), although the SMR for MDS/AML was especially high (SMR = 24.8) and significantly different from PV patients (p_{PV vs ET} < .001). Notably, MDS/AML (EAR = 32.2) and cardiovascular diseases (EAR = 32.0) accounted for a similar number of excess deaths.

ET-specific analyses by age and sex revealed risk patterns similar to PV. Specifically, younger ET patients had higher SMRs from all causes (excluding MPN) than older patients (SMR_{<60 vs ≥60} = 2.3 vs 1.7, p < .001), but larger absolute risks were observed in the ≥ 60 age group (EAR_{<60 vs ≥60} = 74.8 vs. 223.1; Table S4); the magnitude of risks for specific causes generally paralleled those for PV. In noteworthy exceptions, heart disease SMRs were comparable for younger versus older patients (SMR_{<60 vs. ≥60} = 1.8 vs. 1.6, p > .50), while EARs were substantially higher for older patients (EAR_{<60 vs. ≥60} = 9.5 vs. 46.3). Males (SMR = 1.9) had slightly higher risk for all noncancer deaths than females (SMR = 1.7, p = .038).

Individuals with PMF experienced 4.7-times higher risk of all-cause mortality (excluding MPN) (SMR = 4.7, 95% CI = 4.5–5.0, EAR = 768.0) compared to the general population, with noncancer causes accounting for 47% (n = 586) of deaths (SMR = 3.2, EAR = 313.1). SMRs for noncancer deaths from infections, benign hematologic disorders, digestive diseases, renal diseases, and adverse events were increased > 4-fold following PMF, while approximately 2-fold elevated SMRs were seen for endocrine disorders, cerebrovascular disease, heart diseases, and COPD. The greatest noncancer mortality EARs were from heart disease (EAR = 71.3), infections (EAR = 65.6), and benign hematologic disorders (EAR = 43.0). Exceptionally high SMRs for all hematopoietic neoplasms (excluding MPNs) were observed, with MDS/AML (SMR = 188.3) accounting for most of the excess deaths (EAR = 302.2).

PMF-specific analyses stratified by age and sex demonstrated that SMRs for all causes (excluding MPN), all noncancers, all hematopoietic neoplasms (excluding MPN), and MDS/AML were significantly higher among PMF patients < 60 years versus ≥ 60 years of age (Table S5); however, the older age group sustained the greatest burden of deaths from each of these causes. Infections, heart disease, and benign hematologic disorders accounted for most noncancer excess deaths among both age groups. Relative risk of death from all causes (excluding MPN) were significantly increased among males (SMR = 4.7) and females (SMR = 4.8; p = > .50). The SMRs from heart disease, adverse events, and MDS/AML were significantly higher among females than males. With the exception of heart disease (EAR_males = 62.7; EAR_females = 81.9) and adverse events (EAR_males = 21.0; EAR_females = 30.4), the death burden from other specific causes of noncancer deaths, all solid neoplasms, lung and bronchus cancers, all hematopoietic neoplasms (excluding MPN), and MDS/AML predominated among males.

Overall, we found that individuals in the United States with PV, ET, and PMF experienced significantly increased mortality risks from noncancer causes and hematologic neoplasms, with heart disease, cerebrovascular disease, COPD, benign hematologic disorders, and infections, accounting for the majority of excess noncancer deaths. PMF patients had a substantially higher mortality burden overall and for many specific causes of death than those with PV or ET. While age- and sex-specific patterns across MPNs are highlighted, all subgroups had higher noncancer- and MDS/AML-related mortality compared to the general population.

We found significantly increased risks for heart disease following PV, ET, and PMF, with the latter experiencing the highest mortality burden. Overall risk of death from cerebrovascular disease was also increased after an MPN diagnosis, although with fewer excess deaths than observed for heart disease. Chronic inflammation and overproduction of inflammatory cytokines in the classical MPNs is thought to initiate and drive the development of premature atherosclerosis through JAK and other MPN-associated mutation pathways.^1-3

We found significantly increased SMRs for respiratory diseases and COPD for all MPNs although patients with PV and PMF contributed disproportionately to these excess deaths. Our study augments findings from a Danish study that found increased risks of similar magnitude for respiratory mortality among all classical MPNs combined.⁴ While the mechanisms underlying increased respiratory mortality in MPNs are uncertain, activation of inflammatory pathways and therapies administered for MPN may contribute to these findings.^3-5

Mortality from benign hematologic disorders was increased across all MPNs, with disproportionately increased SMRs and excess deaths following PMF. Bleeding related to cytopenias from cytoreductive therapy or marrow fibrosis, platelet dysfunction from anti-platelet therapy, and acquired coagulopathies (e.g., von Willebrand syndrome, therapeutic anticoagulation) could contribute to these deaths.

Infection-related deaths were increased for all MPNs with the highest risks following PMF. Risk of hospitalization from infection was also identified among MPN patients in Sweden, irrespective of common cytoreductive treatments, with the highest risks of infections following PMF.⁶ Immune dysfunction and dysregulated chronic inflammation inherent to MPNs could play a role in the infection-related deaths we observed.

Strengths of our study included the large number of individuals diagnosed with MPNs during a contemporary era encompassing driver mutation testing. Our study is limited by likely under-reporting of MPNs to cancer registries, misclassification, and lack of information on MPN treatment. Furthermore, we cannot exclude potential misclassification of cause of death based on limitations in coding of death certificates.

In summary, we noted some distinct mortality patterns by MPN subtype, age, and sex. The increased risk of death following an MPN diagnosis during a contemporary era suggests that additional measures are needed to decrease mortality.

在美国，经典骨髓增生性肿瘤 (MPN) 的异质亚型——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)——中当代、基于人群、特定原因的死亡风险需要告知病人护理。因此，我们利用 21 世纪在监测、流行病学和最终结果 (SEER) 计划中诊断出的 MPN 病例来量化 PV、ET 和 PMF 的特定原因死亡风险和相关的死亡负担，总体以及按年龄和性别。

我们纳入了 2001-2016 年期间（随访至 2017 年）在 17 个 SEER 癌症登记区的成人（20-84 岁）居民中诊断出的所有首次原发性 PV、ET 和 PMF 病例。使用标准化死亡率（SMR；观察/预期）估计死亡的相对风险，根据 MPN 亚型计算并按诊断年龄和性别分层。使用泊松回归模型和似然法对亚组之间 SMR 的差异进行显着性检验。我们还计算了每 10 000 人年的超额绝对风险 (EAR) 和估计的 MPN 亚型特异性累积死亡率。有关描述 SEER 计划、研究人群、疾病分组和统计方法的更多详细信息，请参阅支持信息中的方法部分。

我们确定了 13340 名 PV 患者、12346 名 ET 患者和 3230 名 PMF 患者（表 1）。在诊断出 PV、ET 和 PMF 后，平均随访时间分别为 6.5、6.0 和 4.0 年。MPN 占 PV 和 ET 诊断后特定原因死亡的 < 10%，PMF 后占 34%（表 S1）。

每个 MPN 的全因死亡率都超过了类似年龄的一般人群，PV、ET 和 PMF 的 10 年累计死亡率分别达到 18.3%、12.5% 和 48.5%，<60 岁的个体（一般人群） ：6.8%）和 46.7%、44.7% 和 83.7%，对于 ≥ 60 岁的人群（一般人群：29.1%）（图 S1，表 S2）。对于患有 PV 或 ET 的患者，在整个 10 年的随访期间，非癌症死亡的累积死亡率远远超过癌症死亡。相反，对于 PMF，所有非癌症、所有血液肿瘤（不包括 MPN）和 MPN 的累积死亡发生率普遍相似地升高，而所有实体瘤的死亡在整个随访期间仍然很低。

与普通人群的预期相比，PV 患者的全因死亡风险（不包括 MPN）增加了 90%（SMR = 1.9，95% CI 1.8–2.0，EAR = 172.1；表 1）。这些死亡中将近 75%（n = 2279；SMR = 2.0，EAR = 131.1）是由于非癌症原因造成的，观察到感染（包括败血症和呼吸道感染）的 SMR 显着增加了 1.8-2.7 倍；消化系统疾病，包括肝病；脑血管疾病; 心血管疾病，包括心脏病；和呼吸系统疾病，包括慢性阻塞性肺病 (COPD)；良性血液病的风险增加 4.3 倍。非癌症超额死亡/10 000 人年的最大负担是由于心脏病 (EAR = 42.7)，COPD、脑血管疾病、和感染（EARs = 11-21）。MDS/AML（SMR = 12.9，EAR = 17.6）解释了大多数因肿瘤死亡的相对风险和超额风险。

在 PV 的年龄和性别特异性分析中， 与年长个体（SMR _≥60  = 1.7，p  < .001）相比，年轻人（SMR _<60 = 2.8）死亡的所有原因（不包括 MPN）的相对风险更高，但老年患者的死亡人数不成比例（EAR _<60  = 126.3 与 EAR _≥60  = 221.8；表 S3）。脑血管疾病、心脏病和 COPD 导致的 SMR 在年龄 < 60 岁和≥ 60 岁的人群中发生率显着升高，并且在女性中观察到心脏病、COPD、不良事件和 MDS/AML 的 SMR 显着高于男性。无论年龄如何，心脏病在非 MPN 死亡中的 EAR 最高（EAR _<60  = 36.0；EAR _≥60 = 50.1) 和性别（EAR_男性 = 41.9；EAR_女性 = 44.2）。

在诊断为 ET 后，非 MPN 死亡的风险也显着增加（SMR = 1.8，95% CI = 1.8–1.9，EAR = 149.1）。非癌症原因的 SMR 通常与 PV 相似，但大多数结果的幅度较小，感染、消化系统疾病、脑血管疾病、心脏病、COPD、肾炎/肾病和不良事件的 SMR 范围为 1.7 至 2.2。然而，观察到良性血液病的死亡风险显着升高（SMR _ET  = 12.5；p _{PV 与 ET}  < .001）和 COPD 的风险较低（SMR _ET  = 1.8；p _{PV 与 ET} < .001) ET 与 PV 相比。尽管 MDS/AML 的 SMR 特别高 (SMR = 24.8) 并且与 PV 患者有显着差异（ p _{PV 与 ET} < .001），但 ET 后实体癌导致的死亡并未超出预期（SMR = 1.0 ）。值得注意的是，MDS/AML (EAR = 32.2) 和心血管疾病 (EAR = 32.0) 造成的超额死亡人数相似。

按年龄和性别进行的 ET 特定分析揭示了与 PV 相似的风险模式。具体而言，较年轻的 ET 患者由于所有原因（不包括 MPN）比老年患者具有更高的 SMR（SMR _{<60 vs ≥60}  = 2.3 vs 1.7，p  <.001），但在 ≥ 60 年龄组中观察到更大的绝对风险（EAR _{<60 与 ≥60}  = 74.8 与 223.1；表 S4）；特定原因的风险程度通常与 PV 的风险程度相当。在值得注意的例外情况下，年轻患者与老年患者的心脏病 SMR 相当（SMR _{<60 与 ≥60}  = 1.8 与 1.6，p  > .50），而老年患者的 EAR 明显更高（EAR _{<60 与 ≥60} = 9.5 对比 46.3）。男性 (SMR = 1.9) 的所有非癌症死亡风险略高于女性 (SMR = 1.7, p  = .038)。

与一般人群相比，PMF 患者的全因死亡率（不包括 MPN）风险高 4.7 倍（SMR = 4.7，95% CI = 4.5–5.0，EAR = 768.0），非癌症原因占 47%（n = 586）死亡（SMR = 3.2，EAR = 313.1）。感染、良性血液病、消化系统疾病、肾脏疾病和不良事件引起的非癌症死亡的 SMR 在 PMF 后增加了 > 4 倍，而内分泌失调、脑血管疾病、心脏病和 COPD 的 SMR 增加了约 2 倍. 最大的非癌症死亡率 EARs 来自心脏病 (EAR = 71.3)、感染 (EAR = 65.6) 和良性血液病 (EAR = 43.0)。所有造血系统肿瘤（不包括 MPN）均观察到异常高的 SMR，MDS/AML（SMR = 188。

按年龄和性别分层的 PMF 特异性分析表明，所有原因（不包括 MPN）、所有非癌症、所有造血系统肿瘤（不包括 MPN）和 MDS/AML 的 SMR 在 60 岁以下的 PMF 患者中显着高于 60 岁以上的患者（表 S5）；然而，年长的年龄组因这些原因中的每一个而承受的死亡负担最大。在这两个年龄组中，感染、心脏病和良性血液病是造成非癌症死亡人数最多的原因。男性 (SMR = 4.7) 和女性 (SMR = 4.8; p = > .50)的全因死亡相对风险（不包括 MPN）显着增加。来自心脏病、不良事件和 MDS/AML 的 SMR 在女性中显着高于男性。除了心脏病（EAR_男性 = 62.7; EAR_女性 = 81.9）和不良事件（EAR_男性 = 21.0；EAR_女性 = 30.4）、非癌症死亡的其他特定原因、所有实体瘤、肺癌和支气管癌、所有造血系统肿瘤（不包括 MPN）和 MDS 的死亡负担/AML 在男性中占主导地位。

总体而言，我们发现美国患有 PV、ET 和 PMF 的人死于非癌症原因和血液肿瘤的风险显着增加，其中心脏病、脑血管疾病、COPD、良性血液病和感染占大多数过多的非癌症死亡。与 PV 或 ET 患者相比，PMF 患者的总体死亡率和许多特定死因的死亡负担要高得多。虽然强调了 MPN 中的年龄和性别特定模式，但与一般人群相比，所有亚组的非癌症和 MDS/AML 相关死亡率都更高。

我们发现 PV、ET 和 PMF 后心脏病的风险显着增加，其中后者的死亡率最高。诊断为 MPN 后，脑血管疾病死亡的总体风险也有所增加，但与心脏病相比，额外死亡人数较少。经典 MPN 中的慢性炎症和炎性细胞因子的过度产生被认为通过 JAK 和其他 MPN 相关突变途径启动和推动过早动脉粥样硬化的发展。^1-3

我们发现所有 MPN 的呼吸系统疾病和 COPD 的 SMR 显着增加，尽管 PV 和 PMF 患者对这些过量死亡的贡献不成比例。我们的研究扩充了一项丹麦研究的结果，该研究发现所有经典 MPN 合并后呼吸系统死亡率的风险增加幅度相似。⁴虽然 MPN 呼吸道死亡率增加的潜在机制尚不确定，但炎症通路的激活和针对 MPN 的治疗可能有助于这些发现。^3-5

所有 MPN 的良性血液病死亡率均增加，SMR 不成比例地增加，PMF 后死亡人数过多。与细胞减灭治疗或骨髓纤维化引起的血细胞减少、抗血小板治疗引起的血小板功能障碍以及获得性凝血病（例如，冯维勒布兰德综合征、治疗性抗凝）相关的出血可能导致这些死亡。

PMF 后风险最高的所有 MPN 的感染相关死亡均有所增加。在瑞典的 MPN 患者中也发现了因感染住院的风险，与常见的细胞减灭治疗无关，PMF 后感染的风险最高。⁶ MPN 固有的免疫功能障碍和失调的慢性炎症可能在我们观察到的感染相关死亡中发挥作用。

我们研究的优势包括在当代包括驱动程序突变测试期间诊断出患有 MPN 的大量个体。我们的研究受到癌症登记处 MPN 可能报告不足、错误分类以及缺乏 MPN 治疗信息的限制。此外，我们不能排除基于死亡证明编码限制的潜在死因错误分类。

总之，我们注意到一些不同的 MPN 亚型、年龄和性别的死亡率模式。在当代，MPN 诊断后死亡风险增加表明需要采取额外措施来降低死亡率。