Treatment of Cancer-Associated Thrombosis: Recent Advances, Unmet Needs, and Future Direction

Abstract Cancer-associated thrombosis, with the incidence rising over the years, is associated with significant morbidity and mortality in patients with cancer. Recent advances in the treatment of cancer-associated venous thromboembolism (VTE) include the introduction of direct oral anticoagulants (DOACs), which provide a more convenient and effective option than low-molecular-weight heparin (LMWH). Nonetheless, important unmet needs remain including an increased risk of bleeding in certain patient subgroups such as those with gastroesophageal cancer, concerns about drug-drug interactions, and management of patients with severe renal impairment. Although DOACs are more convenient than LMWH, persistence can decline over time. Factor XI inhibitors have potential safety advantages over DOACs because factor XI appears to be essential for thrombosis but not hemostasis. In phase II trials, some factor XI inhibitors were superior to enoxaparin for the prevention of VTE after knee replacement surgery without increasing the risk of bleeding. Ongoing trials are assessing the efficacy and safety of factor XI inhibitors for the treatment of cancer-associated VTE.


Introduction
Patients with cancer are at high risk of venous thromboembolism (VTE), which mainly includes upper or lower extremity deep vein thrombosis and pulmonary embolism (PE). 1 The 6-month VTE risk in patients with cancer is up to 12-fold higher than that in the general population and up to 23-fold higher in patients with cancer receiving chemotherapy or targeted therapy. 2 The risk of VTE depends on the type of cancer and is highest in patients with pancreatic cancer, lymphoma (Hodgkin and non-Hodgkin) and ovarian cancer, and lower in those with melanoma. 2Patient and treatment-related characteristics also affect the risk of VTE.Prior VTE, metastatic disease, and the use of chemotherapy or targeted therapy increase the risk. 2,3Additionally, biomarkers such as d-dimer, soluble p-selectin, and more are independent predictive risk factors for cancer-associated VTE. 3 Finally, the 12-month cumulative incidence of VTE over the last 2 decades has increased 3-fold among patients with cancer and up to 6-fold in those receiving chemotherapy or targeted therapy. 2 Therefore, VTE is an increasingly common problem in the cancer population.
VTE in patients with cancer is associated with significant morbidity, hospitalizations, and can interfere or delay potentially curative cancer treatments such as surgery. 4,5VTE and arterial thromboembolism have been reported as the second most common cause of death in cancer patients after tumor progression. 4,6Furthermore, patients with cancer are more likely to have bleeding complications (12-month cumulative incidence of major bleeding: 12.4%, 95% confidence interval [CI] 6.5-18.2) and recurrent VTE despite anticoagulation therapy (incidence rate: 9.6 [95% CI 8.8-10.4]per 100 person-years) compared with those without cancer. 7,8oth recurrent VTE and bleeding complications are associated with lower quality of life and an increase in healthcare costs. 5,7The diagnosis of VTE can be distressing for patients, particularly in those with little support or knowledge about its diagnosis and treatment. 90][11][12] The purpose of this narrative review is to summarize the advances in the treatment of cancer-associated VTE, outline key unmet needs with the current treatment, and discuss how factor XI inhibitors may address the current knowledge gaps.

Evolution of the Treatment of Cancer-Associated VTE
Historically, treatment of acute VTE started with a rapidly acting parental anticoagulant (low-molecular-weight heparin [LMWH], fondaparinux, or unfractionated heparin) overlapped with and followed by a vitamin K antagonist (VKA) such as warfarin.However, in patients with cancer, this approach is problematic because of multiple drug-drug interactions (DDIs) with VKAs that reduce or potentiate their anticoagulant effects and unpredictable gastrointestinal (GI) absorption because of vomiting, diarrhea, or malnutrition.The long half-life of VKAs also complicates treatment in the setting of thrombocytopenia or procedures which are common in patients with cancer.The consortium linking oncology to thrombosis trial was the first randomized controlled trial to demonstrate that LMWH (dalteparin) monotherapy was more effective than warfarin for the prevention of recurrence in patients with cancer-associated VTE and did not significantly increase the risk of bleeding. 13A meta-analysis of 11 trials comparing LMWH with VKAs for treatment of cancer-associated VTE (including consortium linking oncology to thrombosis, CATCH, and others, N = 2777) confirmed the superiority of LMWH over VKAs in preventing recurrent VTE (LMWH vs. VKAs, risk ratio [RR] 0.58, 95% CI 0.45-0.75),with a comparable risk of major bleeding (RR 0.99, 95% CI 0.67-1.45). 14,15Hence, LMWH became the standard of care for treatment of cancer-associated VTE until the introduction of the direct oral anticoagulants (DOACs).However, LMWH is expensive, requires burdensome once or twice daily subcutaneous injections, and is associated with declining persistence over time. 16hese limitations could explain why, until the introduction of the DOACs, VKAs continued to be used in patients with cancer-associated thrombosis. 16ver the past decade, the DOACs have become the anticoagulants of choice for treatment and prevention of VTE in the general population because unlike VKAs, they can be given in fixed doses without routine anticoagulation monitoring. 17 meta-analysis of the pivotal phase III trials that compared the DOACs with VKAs in patients with VTE (N = 27 023) revealed a similar rate of recurrence but a 40% lower rate of major bleeding with the DOACs than VKAs.18 These trials included 1582 patients (5.9%) with active cancer.Analysis in the cancer subgroup showed that compared with VKAs, the DOACs were associated with a significant reduction in recurrent VTE (RR 0.57, 95% CI 0.36-0.91)with no significant difference in major bleeding (RR 0.77, 95% CI 0.44-1.33).18 However, the definition of cancer status varied among different studies, and the patients with cancer included in these studies were likely at lower risk than those enrolled in trials comparing VKAs with LMWH because the rates of recurrent VTE and major bleeding risk in these patients with cancer were lower.19 Nonetheless, these promising results prompted trials comparing DOACs with LMWH in patients with cancer-associated VTE.
1][22][23][24] Metaanalyses of these RTCs showed that DOACs significantly reduced the risk of recurrent VTE compared with dalteparin (hazard ratio [HR] 0.63, 95% CI, 0.47-0.86),but were associated with an increased, yet not statistically significant, risk of major bleeding (HR 1.26, 95% CI, 0.84-1.90)and a significantly increased risk of clinically relevant non-major bleeding (HR 1.48, 95% CI, 1.18-1.85). 24,25Major international guidelines have since then incorporated DOACs as one of the anticoagulants of choice in most patients with cancer except for those considered at high risk of bleeding with a particular emphasis on unresected GI and potentially genitourinary (GU) malignancies. 26,27

Knowledge Gaps and Unmet Needs in the Current Management of Cancer-Associated VTE
DOACs are not without problems (Fig. 1).In the Hokusai VTE cancer and Select-D trials, the risk of major hemorrhage was greater with edoxaban or rivaroxaban than with dalteparin. 20,21,28Although the rate of major bleeding with apixaban was similar to that with dalteparin in the 2 more recent trials, 22,23 a meta-analysis demonstrated a 4.3% risk of major bleeding with DOACs at 6 months and an increased risk of major GI bleeding with DOACs compared with LMWH, especially in patients with unresected luminal GI tumors. 25here was also an increased risk of major GU bleeding associated with DOACs compared with LMWH. 29Recent guidelines have embraced these findings and suggest LMWH over DOACs in these patients, a vulnerable population at particularly high risk of bleeding with unmet needs for a safer anticoagulant option. 26,27here are other considerations with the current anticoagulation management for patients with cancer-associated VTE, including potential DDIs with DOACs, especially with medications affecting the cytochrome (CYP) 3A4 and P-glycoprotein (P-gp) pathways, which can increase the Rates are DOAC versus LMWH, at 6 months except for CASTA DIVA where follow-up was 3 months; HR is followed by 95% confidence interval in the parenthesis.
Abbreviations: CRNMB, clinically relevant non-major bleeding; DOAC, direct oral anticoagulant; HR, hazard ratio; LMWH, low-molecular weight heparin; MB, major bleeding; NR, not reported; SHR, subdistribution hazard ratio; VTE, venous thromboembolism.1][32] Many drugs used for cancer treatment affect these pathways and may be a concern in patients taking DOACs, as summarized extensively in previous reviews. 30,31,33However, much of the evidence remains to be based on pharmacokinetic and pharmacodynamic data only, and more clinically relevant data are needed. 34In addition, renal or hepatic dysfunction are common in cancer patients.Renal dysfunction can lead to drug accumulation, which can increase the risk of bleeding with DOACs.Severe liver dysfunction is also problematic because the DOACs are metabolized in the liver and their efficacy and safety in patients with severe liver disease have not been evaluated.
Another problem with the DOACs is the lack of data on the efficacy and safety of the lower dose regimens of rivaroxaban or apixaban for secondary prevention in patients with active cancer or in those at high risk for recurrence.The ongoing trial comparing the treatment and prophylactic doses of apixaban for secondary prevention in patients who have received at least 6 months of full-dose treatment for cancer-associated VTE is designed to address this question (API-CAT trial, NCT03692065). 35Finally, because patients with cancer-associated VTE often require prolonged anticoagulation therapy, persistence to the DOACs taken once or twice daily often decreases over time, which can lead to VTE recurrence. 16Therefore, anticoagulants that are safer than the DOACs, have no DDIs, are not metabolized in the liver or cleared via the kidneys, and can be given once monthly would simplify the treatment of cancer-associated VTE.

Next-Generation Anticoagulants
Factor XI (FXI) inhibitors have the potential to be safer than DOACs.FXI is a key component of the intrinsic coagulation pathway (Fig. 2).Intrinsic pathway plays an important role in cancer-associated hypercoagulability, as shown by a recent study that extracellular vesicles from various cancer cell lines can activate FXII and initiate the intrinsic pathway. 36FXI can be activated by FXIIa or by thrombin.Thrombosis is triggered by tissue factor, which induces the generation of small amounts of thrombin.Feedback activation of FXI amplifies thrombin generation, which drives thrombus expansion and stabilization.Therefore, FXI is thought to be essential for thrombosis.
In contrast to its essential role in thrombosis, FXI is likely dispensable for hemostasis, which is a primarily extravascular event whereby the hemostatic plug forms at sites of vessel wall injury to seal the leak.Hemostasis is triggered by the high concentrations of tissue factor in the adventitia, the hemostatic envelope that surrounds blood vessels.These high concentrations of tissue factor trigger explosive thrombin generation much like the rapid clotting observed when tissue thromboplastin is added to plasma to measure the prothrombin time.With such explosive thrombin generation, there is little need for amplification by thrombin-mediated activation of FXI.Therefore, FXI inhibitors have the potential to attenuate thrombosis with little or no disruption of hemostasis (Fig. 2).
Epidemiological data support the role of FXI in thrombosis.Elevated FXI levels were associated with an increased risk of VTE compared with lower FXI levels (odds ratio [OR] 2.2, 95% CI, 1.5-3.2) in a large population-based case-control study. 37Likewise, using data from 371 695 participants in the United Kingdom Biobank and 2 large-scale genome-wide association studies, genetic disposition to lower FXI levels was associated with reduced risks of venous thrombosis (OR 0.1, 95% CI 0.07-0.14;P = 3 × 10 −43 ) and ischemic stroke (OR 0.47, 95% CI 0.36-0.61;P = 2 × 10 −8 ) without an increased risk of major bleeding (OR 0.7, 95% CI 0.45-1.04;P = .0739). 38These findings are in keeping with the observation that, the risk of ischemic stroke and VTE is lower in patients with congenital FXI deficiency than in the general population.The findings also align with the fact that patients with Figure 2. The role of factor XI (FXI)in the coagulation cascade in physiological hemostasis and pathological thrombosis.Thrombosis: Thrombus growth depends on activation of FXI to amplify the process (the color-highlighted pathways are the predominant pathways here, including intrinsic and common pathways, while the non-dominant pathways are grayed-out).Thrombin and FXIIa are important activator of FXI.Hemostasis: FVII or FVIIa binds to extravascular TF leading to explosive thrombin generation to convert fibrinogen to fibrin (the color-highlighted pathways are extrinsic and common pathways and are the predominant pathways here, while the non-dominant pathways are grayed-out).While FXI is also activated by thrombin generated early in hemostasis and contributes to sustained thrombin generation, the intrinsic pathway is not predominantly needed, explaining why FXI is not as crucial in hemostasis.
][44][45] Fesomersen, which blocks hepatic synthesis of FXI, requires 3-4 weeks of subcutaneous administration to lower FXI levels into the therapeutic range effect.In contrast, milvexian has a rapid onset of action after oral administration as do the FXI-directed antibodies if given intravenously.All trials compared the FXI inhibitors with enoxaparin (apixaban was used as an additional exploratory control in the osocimab trial).Non-inferior or superior antithrombotic efficacy with selected doses has been shown with all FXI inhibitors (Table 3).The risk of clinically relevant bleeding was low with effective doses of the FXI inhibitors (1%-2%) and similar to that with enoxaparin.The observation that FXI inhibitors were at least as effective as enoxaparin, which inhibits FXa and thrombin, suggests that even though VTE is likely triggered by tissue factor exposed at the surgical site, feedback activation of FXI by thrombin appears to be an important driver, a process that is blocked with FXI inhibition.
There are more ongoing or upcoming clinical trials to investigate various FXI inhibitors for different indications, which are summarized in Table 4.

Pharmacology of Abelacimab
Abelacimab is a fully humanized monoclonal antibody that binds to FXI with high affinity and locks it in the zymogen confirmation, preventing its activation by FXIIa and thrombin. 46,47It has been evaluated in 3 phase I human studies and 2 phase II studies and is found to be safe and promising. 46The pharmacokinetics and pharmacodynamic models obtained from phase I/II studies showed that abelacimab has a half-life of approximately 20 days.Intravenous administration produces rapid and dose-dependent inhibition of FXI.No infusions were stopped due to hypersensitivity reactions and no anti-drug antibodies were detected. 46

Abelacimab for Treatment of Cancer-Associated VTE
Abelacimab could potentially address most of the unmet needs in the current management of cancer-associated VTE (Fig. 1).The benefit of low bleeding potential of abelacimab, if confirmed, will provide a safer anticoagulant option for patients with high risk of bleeding, as well as those with cancer or in need of concomitant antiplatelet therapy. 46The 20-day half-life of abelacimab allows for once monthly subcutaneous dosing, which could improve

Characteristics
Buller et al 42 Weitz et al 43 Verhamme et al 44 Weitz et al 45  persistence. 16Parenteral administration circumvents the potential for poor drug absorption in cancer patients with GI disturbances.Abelacimab is not cleared via the kidneys or metabolized in the liver. 46Therefore, its use is unaffected by severe kidney or hepatic dysfunction.Finally, because catheter-related thrombosis is triggered by activation of FXII, FXI inhibitors may prove more effective than DOACs for prevention or treatment of central venous catheter thrombosis.

Outcomes
Buller et al 42 Weitz et al 43 Verhamme et al 44 Weitz et al 45  Two phase III multicenter RCTs are underway to evaluate the efficacy and safety of abelacimab for the treatment of cancer-associated VTE, the ASTER, and MAGNOLIA trials (Table 4).The ASTER trial (NCT05171049) is comparing abelacimab with apixaban for treatment of VTE in patients with cancer-associated VTE for which a DOAC treatment is intended, whereas the MAGNOLIA trial (NCT05171075) is specifically assessing the efficacy and safety of abelacimab comparing with dalteparin for treatment of VTE in patients with intact, unresectable GI or GU cancers.In both trials, abelacimab is administered as an intravenous infusion on day 1 (to achieve rapid FXI inhibition), followed by monthly subcutaneous injection (to maintain FXI inhibition) for a total of 6 months.The primary efficacy outcome for both trials is the time to first VTE recurrence consisting of new proximal deep vein thrombosis, and new or fatal PE or unexpected death for which PE cannot be excluded.Secondary outcomes include time to the first major or CRNM bleed and net clinical benefit, defined as survival without VTE recurrence, major or CRNM bleeds.

VTE
Several caveats are worth noting with the introduction of FXI inhibitors in clinical use.FXI inhibition will result in a prolonged activated partial thromboplastin time (aPTT), as FXI is essential in initiating clot formation in vitro as part of the aPTT assay.This might cause concerns about hemostasis, but aPTT and/or FXI levels are poorly associated with true bleeding phenotypes in patients with congenital FXI deficiency (and remains to be seen in those receiving FXI inhibitors).This is because, unlike what happens in vitro, the physiologic hemostasis in vivo is mainly driven by the tissue factor-FVIIa (Fig. 2). 48Therefore, the aPTT is likely to be a poor predictor of the risk of bleeding in patients receiving FXI inhibitors, although it could be a good marker for the presence of the drug. 48The resultant prolonged aPTT could also complicate the monitoring of alternative anticoagulants such as unfractionated heparin (if used), which can be addressed by monitoring heparin anti-Xa levels (by chromogenic assays).In addition, some FXI inhibitors such as abelacimab have a long half-life (20 days), while studies to date showed that FXI inhibitors are associated with bleeding rates as low as, or lower than standard anticoagulants, inevitable scenarios such as hemorrhage, urgent procedures, or thrombocytopenia will occur, particularly in patients with cancer, and the optimal management strategies in these settings remain to be elucidated.One recent publication has begun the process of developing a proposal to apply similar approaches as managing those with congenital FXI deficiency patients, including the use of antifibrinolytic agents, fibrin glue, and/ or low-dose recombinant factor VIIa. 49 Fresh frozen plasma or FXI concentrates are less likely to be effective given rapid neutralization of these exogenous FXI by excess free abelacimab.Further development and validation of effective and safe protocols are needed.

Conclusion
In conclusion, thrombosis remains to be a significant source of morbidity and mortality in patients with Table 4. Selected ongoing and upcoming trials of factor XI inhibitors (not including published studies, which were discussed in the text and Tables 2 and 3).cancer.Major advances in anticoagulant treatments, such as DOACs, have significantly raised the bar for effective and safe anticoagulant options in recent years, but further improvement in the care of this vulnerable population is required.Factor XI inhibitors may provide a potential novel approach to address current unmet needs, including the risks of bleeding, DDIs, liver or kidney dysfunction, and long-term persistence in the treatment of cancer-associated thrombosis.

Figure 1 .
Figure 1.Knowledge gaps and unmet needs related to current anticoagulants for the management of cancer-associated thrombosis (center) and how factor XI inhibitors could address these issues (peripheral).

Table 2 .
Randomized controlled trials of factor XI inhibitors in elective knee arthroplasty (trial characteristics).

Table 3 .
Randomized controlled trials of factor XI inhibitors in elective knee arthroplasty (outcomes).
*The primary