Direct Oral Anticoagulants Show Prophylactic Potential in MPN-Induced Thrombosis

Srikanth Nagalla, MD, director, Hematology Oncology Fellowship Program, Harold C. Simmons Comprehensive Cancer Center, and associate professor of medicine, UT Southwestern Medical Center

Srikanth Nagalla, MD

Direct oral anticoagulants (DOACs) are commonly used in patients with non-myeloproliferative neoplasm (MPN)-associated venous thromboembolic events (VTEs), said Srikanth Nagalla, MD, adding that these agents are also appropriate for patients with MPN-associated VTEs.

According to a small retrospective analysis presented at the 2019 ASH Annual Meeting, the majority of patients who had an MPN-associated VTE did not experience recurrent VTE if they received a DOAC. Among 24 patients, 16 received a DOACs up front and 8 were switched from vitamin K antagonists or heparin to a DOAC. At the median follow-up period of 2.2 years, 23 patients had not experienced a VTE recurrence.

Although no cases of severe bleeding were reported, 2 patients experienced clinically relevant bleeding. Notably, both patients were receiving aspirin in addition to a DOAC. Although aspirin is commonly given for thromboprophylaxis, Nagalla explained that patients without cardiovascular risk factors may be able to forgo aspirin to reduce the risk of bleeding.

“During the 2019 ASH Annual Meeting, we saw data that solidified that these agents are as effective as low molecular weight heparin, or better than warfarin in some instances, in preventing thrombosis in patients with cancer or a history of cancer, as well as in treating active clots in patients with cancer,” said Nagalla.

In an interview during the 2020 OncLive^® State of Science Summit^™ on Hematologic Malignancies, Nagalla, director of the Hematology Oncology Fellowship Program at the Harold C. Simmons Comprehensive Cancer Center and associate professor of medicine at the UT Southwestern Medical Center, discussed the management of cancer-related thrombosis in MPNs, as well as updates in immune thrombocytopenic purpura (ITP).

OncLive: Could you discuss some of the updates in cancer-related thrombosis that were presented at the 2019 ASH Annual Meeting?

Nagalla: Oncologists are already using DOACs such as dabigatran (Pradaxa), rivaroxaban (Xarelto) and apixaban (Eliquis) for cancer-associated thrombosis. Trials have been published or are ongoing to study thrombosis prevention, specifically for patients with cancer who have an intermediate or high risk of developing thrombosis during chemotherapy. [These agents] have also [shown benefit] in patients who have already had a clot.

The downside is that the risk of bleeding is always higher with anticoagulants in patients with cancer. Overall, that risk should not prevent their use for the prevention of thrombosis in intermediate- and high-risk patients with cancer, as well as for the treatment of deep vein thrombosis or a pulmonary embolism in patients with cancer.

What are some of the challenges that you face in managing cancer-related thrombosis?

Thrombosis management is not straightforward. Many patients could have concomitant thrombocytopenia because their platelet count drops while they’re on chemotherapy. That increases the risk of bleeding, so you need to be careful. Patients with cancer who are receiving chemotherapy could experience decreased renal function. If their renal function creatine clearance is low, some of these agents may not be safe. [In that case], you may want to go back to warfarin, even though we know it’s not that great for patients with cancer.

[Investigators] are putting together [an algorithm] to help us predict which patients are going to develop thrombosis. If we can predict that, we know we’re not going to be using these drugs unnecessarily. We are looking at not only clinical factors. We’re also looking at next-generation sequencing data to try to identify genes that are overexpressed or underexpressed to see whether we can predict which patients with a particular cancer might develop thrombosis. As science evolves, we might be able to do a better job of predicting which patients are at risk of recurrent clots [and be able to treat them accordingly and I hope] with better drugs that have lower rates of bleeding.

Could you shed light on some key trials examining thrombosis in MPNs?

In practice, physicians started using DOACs to treat portal vein thrombosis or cerebral venous thrombosis associated with JAK2-positive or JAK2-negative MPNs, including polycythemia vera, essential thrombocythemia, myelofibrosis, and others.

In this particular study, investigators did a retrospective analysis of patients with MPNs who had thrombosis and received DOACs. Investigators looked at 24 of 102 patients. I believe the study was done in the United Kingdom. Many of these patients had JAK2-positive disease; about 18 patients were JAK2 positive. [These patients are the most] thrombogenic of all the patients with MPNs that I am describing. Overall, these patients did well; they did not have recurrent thrombosis when a DOAC was used. Bleeding did occur, mainly when the drug was used concomitantly with antiplatelet therapy. Generally, we use aspirin for thromboprophylaxis in patients with MPNs. If you use a DOAC in a patient who doesn’t have cardiovascular risk factors and who already had a clot, you could potentially spare them from having to take aspirin.

As a separate note, when aspirin is used for something without an indication in patients who are already taking a DOAC, the risk of bleeding is higher. The bottom line is, 3 articles in the New England Journal of Medicine in 2018 have stated not to use aspirin if there is no clear indication for primary prophylaxis. Previously, the thought was that anyone above age 40 could take a baby aspirin. We have to move away from that assumption. Patients who are on a DOAC should not receive aspirin if there’s no clear-cut indication for it. In the MPN study, in which aspirin was used concomitantly with a DOAC, 3 patients experienced bleeding. DOACs, at least in this small retrospective study, were effective in preventing thrombosis in patients with MPNs.

What are some of the latest developments in ITP?

Fostamatinib (Tavalisse) is used in ITP, mainly in patients who have failed multiple lines of treatment. In a recent study, investigators evaluated fostamatinib as second-line therapy. When the drug was used as second-line therapy, the number of patients who responded to the drug with an increase in their platelet count was higher compared with when it’s used in later lines of treatment. Based on [these data], we may want to use fostamatinib earlier on, especially because not very many patients prefer to get a splenectomy.

Doyle A, Breen K, McLornan DP, et al. Outcomes of patients receiving direct oral anticoagulants for myeloproliferative neoplasm associated venous thromboembolism. Blood. 2019;134(suppl 1; abstr 4183). doi: 10.1182/blood-2019-128170.