Are veterans at increased risk of myeloproliferative neoplasms?
Authors: Christin B. DeStefano, Nicholas Burwick, Drew A. Helmer
Journal: American Journal of Hematology (2024)

Military members are expected to go in harm's way if needed and endure potentially harsh conditions or toxic exposures during training and deployments. For example, Vietnam War Veterans were potentially exposed to Agent Orange, and Persian Gulf War Veterans were potentially exposed to oil well fire smoke, pesticides, chemical warfare, pyridostigmine bromide among other toxins.1, 2 The carcinogen in Agent Orange (2,3,7,8-tetrachlorodibenzo-p-dioxin) binds to and activates the aryl hydrocarbon receptor, a cytosolic receptor that modulates transcription and gene expression and has been associated with a heightened risk of multiple hematologic malignancies including Hodgkin and non-Hodgkin lymphoma and chronic lymphocytic leukemia based on rigorous epidemiologic studies.2 In 2018, the National Academies of Science, Engineering and Medicine (NASEM) was charged with reviewing associations between Agent Orange and myeloproliferative neoplasms (MPNs); there were no published studies in humans, animals or cell lines identified, and as a result of the paucity of epidemiologic studies and biologic plausibility of a connection between Agent Orange exposure and abnormalities in hematopoietic stem cells, the NASEM deemed there to be insufficient evidence to associate Agent Orange with MPNs.2 With regard to the Persian Gulf War, the NASEM acknowledged in the 10th Volume of Gulf War and Health (2016) that not enough latency has passed to tell if deployment to the Persian Gulf War is associated with development of neoplasms.1 Additionally, there was insufficient/inadequate evidence of an association between deployment to the Gulf War and cancer mortality.1 Owing to recall bias, survivorship bias, difficulty measuring the dose or duration of an exposure, individual variability in genetic susceptibility to damage from an exposure, exposures before or after military service and long latency periods after an exposure to cancer development, it is difficult to tell if a service-related exposure increases the risk of an adverse health outcome later in life.3 As a result of challenges to determine whether deployment is associated with future adverse health outcomes, the Veterans Health Administration (VHA) Promise to Address Comprehensive Toxics (PACT) Act mandated changes to expand healthcare benefits and disability compensation to Veterans with conditions presumed to be related to toxin exposure.4 While many malignancies are considered related to toxin exposure in the law, MPNs such as essential thrombocytosis (ET), polycythemia vera (PV), and primary myelofibrosis (PMF) are not. MPNs are rare, clonal disorders characterized by overproduction of differentiated hematopoietic cells that are largely driven by mutations in JAK2 (PV, ET, PMF) but can also be driven by CALR and MPL or other mutations (ET, PMF). Constitutive clonally driven myeloproliferation increases the risks of thrombosis, microcirculatory symptoms, bleeding from acquired von Willebrand disease, constitutional symptoms, and progression to myelofibrosis or acute myeloid leukemia.5, 6 Disease management requires regular office visits, laboratory monitoring, invasive procedures such as bone marrow biopsy, and interventions including regular phlebotomy sessions and utilization of cytoreductive or janus kinase targeted agents. Adding to the burden of this disease, comorbid conditions must be aggressively monitored and managed to avoid potentially morbid and life-threatening MPN complications. Even with such proactive care, patients can become significantly incapacitated due to the progressive and unpredictable nature of the disease. As a result, the diagnosis of an MPN places a significant burden on patients and their families. In this issue of the Journal, Tiu et al. used data from the Veterans Affairs Informatics and Computing Infrastructure (VINCI) to assess period of military service and MPN risk, risk of thrombosis and bleeding, and overall survival (OS). Nearly 500 000 Veterans from Illinois were assessed from January 1, 2006, through January 26, 2023. This study was racially diverse, with 19.2% of included Veterans classified as black. The authors report that Persian Gulf War era Veterans were diagnosed with MPNs at a younger age compared with Korean War era and Vietnam War era Veterans. Additionally, the authors report that Persian Gulf War era Veterans had an increased risk of MPN development compared to Korean War era Veterans (HR 4.92) and Vietnam War era Veterans (2.49), and that Vietnam War era Veterans had a higher risk of MPN development than Korean War era Veterans (HR 1.97). Persian Gulf War era Veterans were more likely to experience thrombosis and bleeding than Vietnam and Korean War era Veterans, and Vietnam War era Veterans were more likely to experience thrombosis and bleeding than Korean War era Veterans. Persian Gulf War era Veterans with MPNs had a significantly shorter OS than Korean and Vietnam War era Veterans with MPNs. The authors conclude that Persian Gulf and Vietnam War era Veterans are at increased risk of MPNs, and that this information has implications for VA benefits policy in accordance with the PACT Act. This study has multiple limitations, including lack of toxic exposure or reliable deployment data, risk of capturing secondary erythrocytosis or thrombocytosis by using a single ICD code for case definitions, lack of mutational data to confirm the presence of clonality, inclusion of only Veterans from Illinois, and varying use of the VHA by era cohorts. Korean and Vietnam War era Veterans were older than Persian Gulf War era Veterans during the study period (only since 2006), which could explain why Persian Gulf War era Veterans were found to have a younger age at diagnosis. The finding that Persian Gulf War era Veterans with MPNs had a shorter OS than Korean and Vietnam War era Veterans could be due to immortal time bias, since Korean and Vietnam War era Veterans with MPNs would be more likely to die prior to the start of the study period in 2006. Despite the many limitations of this retrospective study, the findings suggest that military service could increase the risk of MPNs. For example, the findings that black race was associated with an increased risk of ET, that smoking increased the risk of MPN development, and that MPNs increased the risk of thrombosis and bleeding are consistent with previous reports about MPNs.5, 6 With regard to cancer latency, tumorigenesis is a complex, multi-step process with various branch points, and it has been postulated that somatic mutations do not always accumulate in a predictable and linear fashion after an exposure, making it difficult to ascribe a tumor-initiating driver somatic mutation such as JAK2 to a genotoxic exposure.7 Indeed, it has been shown in phylogenetic analyses that JAK2 mutations or other high-risk driver somatic mutations can occur in-utero or in early childhood,8 begging the question of what type of exposure or event could trigger acquisition of a somatic mutation at such a young age and whether subsequent stressors or exposures to carcinogenic or bone marrow toxic substances, such as during military service, could accelerate clonal expansion and evolution. While acquisition and evolution of toxin-related clonal mutations is critical to study, it is the associated clinical phenotype of MPNs that drives patient disability. Military service or non-service factors could drive disease evolution (stress, inflammation, toxic effects on the bone marrow microenvironment) and may be difficult to assess genomically. Therefore, analysis of ICD codes, while having limitations, potentially enriches cases that are more clinically relevant. In the 11th Update on Veterans and Agent Orange, the NASEM committee recommended that investigators examine existing databases to evaluate MPN risk in Vietnam Veterans.2 Owing to long latency, the 2016 NASEM update on Gulf War and Health recommended that the VHA conduct further studies on cancer incidence, prevalence and mortality, maximize cancer registries and other relevant data sources, have sufficient sample size to account for rare cancers, and report sex- and race/ethnicity-related variables.1 Arguably Tiu et al. have accomplished these recommendations. While proving an increased incidence is difficult owing to limitations such as missing exposure information, incomplete case identification, immortal time bias, and many others, the excess mortality among Persian Gulf War Veterans with MPNs demonstrated by Tiu et al. is concerning. Are we as a society OK with accepting the risk of excess patient deaths while awaiting validation or a higher level of evidence that might not ever exist? Service connection enhances access to VHA care,9 which has been repeatedly shown to match or exceed private sector care.10 The PACT Act mandated an evaluation and improvement in the process of considering health conditions for presumed service connection to expand access to VHA care. Presumed service connection represents critical policy considerations for overcoming the challenges of scientifically proving a causal relationship between an exposure and a health outcome. First, in the absence of individual-level exposure information for each Veteran, presumed service connection makes the connection between the individual and the exposure based on time and place of service. For example, Veterans who set foot in the Republic of Vietnam from 1962 to 1975 have presumed exposure to Agent Orange. Second, additional review and consideration then links a condition of concern to the exposure, for example, Hodgkin or non-Hodgkin's lymphoma for Vietnam Veterans. The NASEM made several recommendations to the VHA for diversifying the types of data used to inform service-connection policy decisions, enhance transparency, and enhance community engagement in the process.4 The recommendations are currently being implemented and evaluated for newly nominated diseases potentially related to Agent Orange or service in the Gulf War era. In this context, the findings of the study by Tiu et al. support consideration of MPNs as presumed service-connected conditions for exposures during military service on and after 1962. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.