The association between myeloproliferative neoplasms (MPNs) and an increased risk of both thrombotic and hemorrhagic complications has been recognized for some time, and cardiovascular events contribute significantly to morbidity and mortality in patients with MPNs. The mechanism behind these associations is not entirely understood, although it is becoming clearer as new studies are completed.
A comprehensive literature review by Orly Leiva, MD, of the Division of Cardiology at New York University Grossman School of Medicine and Department of Medicine at Brigham and Women’s Hospital and Harvard Medical School, and colleagues offered some clarity on the topic. The review, which appeared in JACC: CardioOncology,1 summarized the current state of the science, elucidated connections and clinical implications, and identified research gaps. According to the authors, the commonalities between MPNs and cardiovascular disease (CVD), including somatic mutations and inflammation, warrant closer investigation and may help guide treatment strategies for hematologists and cardiologists in the future.
ASH Clinical News spoke with Dr. Leiva and other experts about the CVD-MPN connection, the underlying mechanisms that have been studied to date, patient care implications, and the pressing questions they hope will be answered in future research.
Somatic Mutations and Increased Inflammation
“In MPNs, in particular, recent knowledge has contributed most to establishing a connection between MPNs and CVD,” said Tiziano Barbui, MD, professor of hematology and scientific director of research at FROM Research Foundation and Papa Giovanni XXIII Hospital in Bergamo, Italy. “A great boost was gained after the discovery of driver somatic mutations. . . . Somatic mutations are currently part of major MPN diagnostic criteria and have been incorporated into scoring systems to identify patients at higher cardiovascular risk.”
MPNs arise from somatic mutations (see FIGURE). These mutations lead to constitutive activation of the Janus associated kinase (JAK)/signal transducer and activator of transcription (STAT)-signaling pathway, which regulates the production of pro-inflammatory cytokines. Mutations in the JAK2, calreticulin (CALR), and myeloproliferative leukemia (MPL) protein genes account for most driver mutations in MPNs. Patients with MPNs also exhibit other mutations that can be associated with increased inflammation, including in tet methylcytosine dioxygenase 2 (TET2), DNA methyltransferase 3 alpha (DNMT3A), and additional sex combs-like 1 (ASXL1) genes.
A mutation in JAK2 confers about a two-fold increased risk of arterial thrombotic events compared with non-JAK2 driver mutations in essential thrombocythemia (ET) and primary myelofibrosis (MF). Additionally, in polycythemia vera (PV), JAK2 mutation accounts for more than 95% of driver mutations and increased JAK2V617F burden of mutant leukocytes in peripheral blood (the variant allele frequency) is associated with increased venous thrombosis.
FIGURE. Oversimplified Schema Illustrating the Spectrum of Disorders of Myelopoiesis
Source: Leiva et al. 2022. CC-BY-NC-ND.
ASXL1 = additional sex combs-like 1; CALR = calreticulin; DNMT3a = DNA methyltransferase 3 alpha; JAK2 = Janus kinase 2; LOX = lysyl oxidase; MPL = myeloproliferative leukemia protein; TET2 = tet methylcytosine dioxygenase 2; TGFβ = transforming growth factor–β.
Patients with MPNs often harbor non-driver mutations in genes commonly associated with clonal hematopoiesis of indeterminate potential (CHIP), including TET2, DNTM3A, and ASXL1. The JAK2V617F mutation is the predominant mutation associated with both CHIP and MPNs and is also the most strongly associated with CVD risk and thrombosis. The presence of CHIP-associated mutations in patients with MPNs is likely associated with worse outcomes; however, their impact on cardiovascular events and outcomes requires further investigation, according to Dr. Leiva and colleagues.
“Of late, the identification of patients with CHIP has ushered in a new area of understanding,” said Brady L. Stein, MD, associate professor of medicine at Northwestern University Feinberg School of Medicine in Chicago. These patients have a mutation but a normal complete blood count (CBC) and are at higher risk of developing a hematologic malignancy, he added.
“This observation was perhaps intuitive for most,” Dr. Stein added. “The finding that was quite illuminating to many was that patients with a low-frequency mutation and a normal CBC still had a higher risk for cardiovascular events. . . . The central link between the mutation, future risk for hematologic malignancies, and cardiovascular events appears mediated through inflammatory stress.”
The discovery that there are common pathophysiologic mechanisms underlying CVD and diseases caused by somatic mutations in bone marrow stem cells “has dramatically altered the way both conditions are viewed and will surely alter treatment strategies,” according to Dr. Leiva and colleagues.
They added that preventing thrombotic events should be a priority to reduce morbidity and mortality in MPNs. Aspirin is commonly used in PV, ET, and to some extent, in patients with primary MF and can also reduce the risk of thrombosis. In PV, research supports phlebotomy to control hematocrit levels to less than 45%, which limits thrombosis and reduces the incidence of cardiovascular events, Dr. Leiva said.
“This is typically accomplished through phlebotomy or cytoreductive therapy,” he explained. “For ET, that’s kind of a double-edged sword because when you do have increased platelet counts, to a certain degree that increases the risk of thrombosis, but then once you get to this extreme platelet count, you have increased risk of bleeding. So, both phlebotomy and cytoreduction serve as a protectant for thrombosis.”
Because of the dual risk of thrombotic complications and hemorrhage, the use of anticoagulation and antiplatelet therapy in primary and secondary prevention of coronary artery disease is complicated in this patient group. Direct oral anticoagulants (DOACs) may more effectively prevent recurrent venous thromboembolism compared with vitamin K antagonists in patients with MPNs, but more investigation is needed, Dr. Leiva and colleagues noted.
Clinicians may also consider targeting the link of inflammation between CVD and MPNs. According to Dr. Stein, one foundation of therapy for MF, and sometimes PV, are JAK inhibitors, although it’s unclear yet whether these therapies can delay disease progression as well as lower the risk of vascular events.
“To an extent, we have some evidence that this strategy is effective in MPNs,” Dr. Stein said. “JAK inhibitors provide an anti-inflammatory effect. [Dr. Leiva et al.] cite some evidence that may suggest that JAK inhibition, likely through an anti-inflammatory effect, may reduce risk for thrombosis in patients with PV and MF. The authors appropriately state that thrombosis was not an endpoint in major clinical trials, so we have to be careful not to over-interpret.”
Unmet Needs & Unanswered Questions
There are numerous research questions that remain to be answered in this field, but the research to date points investigators and clinicians toward screening options and emerging therapies.
“Overlap between MPNs and CVD is a nascent field, so I think there are two pathways that need to be fleshed out,” Dr. Leiva said. “First, we need to have better and bigger epidemiologic studies describing the incidence of heart failure and pulmonary hypertension. . . . The second is to identify any particular risk factors that might be contributing to increased cardiovascular risk in patients with MPNs.”
Dr. Leiva pointed to JAK2 mutation as being a known risk factor, as well as elevated hematocrit and platelet counts. Additional research in these areas will help identify whether MPNs or patient characteristics lead to high risk for CVD. From there, treatment can be initiated to help control it.
“Patients with MPNs have many unmet treatment needs,” Dr. Stein said. “The largest is that we cannot attain complete remissions with medical therapy, as is the case with chronic myeloid leukemia. . . . So first, we need effective medical therapies that can truly modify the natural history of the disease.”
Dr. Stein added that several therapies are under investigation, mostly in MF given its aggressive nature, but also in PV and, to some extent, ET.
Several therapies are being studied in this field, and the idea of precision medicine continues to evolve. Because inflammation is a likely contributor to both MPN pathogenesis and complications, as well as CVD, anti-inflammatory therapies are ripe for further investigation in this realm.
Dr. Leiva and colleagues noted that inhibition of the JAK/STAT pathway with ruxolitinib, a JAK1 and 2 inhibitor, is the only tailored therapy approved by the U.S. Food and Drug Administration for patients with MPNs. Further, they noted that JAK inhibition may decrease thrombosis markers in these patients, but “concerning data should spur the development and evaluation of safety and efficacy of more selective JAK inhibitors.”
A newer therapy being investigated achieves lysyl oxidase (LOX) inhibition, which has been shown to potentially reduce fibrosis in animal studies of primary MF. However, the effect of this inhibition on cardiovascular and thrombotic risk has yet to be explored in human trials.
One challenge for physicians is to correctly gauge a patient’s level of risk for CVD, since the risk-classification between MPNs and thrombosis is not fully refined.
“As outlined [by Dr. Leiva et al.], there are many studies that illuminate the complexity of MPN thrombosis. We need to find surrogates or biomarkers for MPN thrombosis that can be used in clinical practice,” Dr. Stein said.
A goal in the clinical setting could be to start screening patients for CHIP when they have “premature or unexplained coronary artery diseases or stroke in the absence of traditional risk factors,” Dr. Barbui said. He added that next-generation sequencing may help identify specific mutations in patients with MPNs and thrombotic events.
“In addition to evaluating the variant allele function (VAF) for CHIP mutations, in particular for JAK2V617F, it could be useful to search for biomarkers of inflammation that are linked to both the cardiovascular complications and the risk of hematologic transformation,” Dr. Barbui added, specifying high-sensitivity (hs)-CRP and PTX3.
Many larger academic institutions have cardio-oncology centers where patients can receive specialized care, which is becoming more common. In addition, some institutions have opened CHIP clinics with a multidisciplinary focus.
“Of great interest are the initiatives that are summarized in the establishment of CHIP clinics to recognize patients with CVD associated with somatic mutations (i.e., myocardial infarction, aortic aneurism, stroke),” Dr. Barbui said. “The aim of CHIP clinics is to recognize the presence of clonal hematopoiesis and to treat these clonal disorders earlier to eliminate the emergence of new clones and to reduce cardiovascular complications and clonal evolutions.”
Aside from working in specialized centers like these, hematologists have other options for getting the support they need to effectively care for this patient group. For example, prior training and multidisciplinary collaboration can be particularly beneficial.
“Hematologists who care for patients with MPNs have to rely on their internal medicine skills, or at least collaborate closely with primary care and cardiology, given that MPNs are known to be vascular diseases,” Dr. Stein said. “We have to make sure that cardiovascular risk factors are being appropriately modified.”
He noted that after a patient is diagnosed with MPN, it’s common for the focus to be on the blood condition. However, it’s also important to talk to patients about lifestyle factors that can help reduce cardiovascular risk, like exercising, not smoking, monitoring their body weight, and maintaining healthy blood pressure, blood glucose, and cholesterol levels.
“Collaboration with the cardiologist and neurologist can be very useful in some specific cases of thrombotic recurrence,” Dr. Barbui said, specifying that patients should have discussions with specialists and non-physician providers to address cardiovascular issues.
“Our cancer treatments are getting better and better every year, patients are living so much longer, even patients with MPNs have life expectancy in the decades,” Dr. Leiva said. “So, as we get better at treating cancer and hematologic conditions, we start to notice that patients are dying of CVD. We’re doing great with the cancer therapy, and now that they survived or are managing their cancer, we need to focus a lot more on the cardiovascular prevention aspect of their treatment.”
—By Kimberly J. Retzlaff
This summary is published in collaboration with JACC: CardioOncology.
- Leiva O, Hobbs G, Ravid K, Libby P. Cardiovascular disease in myeloproliferative neoplasms: JACC: CardioOncology state-of-the-art review [published online 2022 June 21]. JACC: CardioOncology. doi: 10.1016/j.jaccao.2022.04.002.