Activity Transcript

Jean M. Connors, MD: Hello, I'm Dr Jean Connors. I'm a hematologist and the medical director of the hemostatic and antithrombotic stewardship programs and the anticoagulation management services at both Brigham and Women's Hospital and the Dana-Farber Cancer Institute. I'm also an associate professor of medicine at Harvard Medical School in Boston, Massachusetts, and I'd like to welcome you to this program, Evolving Approaches to Treating Thrombosis in Cancer from Concept to Clinic. Joining me today are my outstanding colleagues, Dr. Alok Khorana and Dr. Jeff Weitz, and I'm going to allow them both to introduce themselves. Dr. Khorana?

Alok A. Khorana, MD : Hi, thanks for having me on this program. My name is Alok Khorana. I'm a medical oncologist and director of the GI cancer program at the Cleveland Clinic in Cleveland, Ohio.

Jeffrey I. Weitz, MD, FRCP(C), FACP, FCCP : I'm Jeff Weitz, and I'm a professor of medicine in biochemistry at McMaster University, and like you, I'm also a hematologist who treats a lot of patients with cancer-associated thrombosis.

Dr Connors: Excellent. I'm just going to set the background, and I think, anybody who works with patients who have cancer, whether it be on the medical oncology side, the surgical oncology side, or as hematologists who get called in to consult, we recognize that patients who have cancer have an increased risk of developing thrombosis compared to patients who don't have cancer. Particularly VTE, venous thromboembolism, is found to be the second leading cause of death in patients who have cancer, second only to the cancer itself.

And we know that patients can even be at increased risk of arterial thromboembolism, particularly stroke in advanced stage cancers, but also MI. Now there are a number of factors that are cancer specific that increase the risk of thrombosis, including the type of cancer, what organ it originates from, the stage, whether it's early or advanced, and treatment factors, including hospitalization itself or surgery, both of which are risks for patients who don't have cancer. But then chemotherapy, hormonal therapies, antiangiogenic therapies, erythropoiesis-stimulating agent and others all are unique risk factors for our patients with cancer that increase their risk for thrombosis.

Now when patients who have cancer do develop a venous thrombosis in particular, we know that they also have a higher risk of anticoagulation-related bleeding compared to patients on anticoagulation who don't have cancer. And interestingly, over the last 20 years it's been shown that the incidence of cancer-associated thrombosis is increasing due to many factors, some of which are outstandingly great in terms of improved treatments for patients with cancer so that they are living longer and have a longer period of time to develop thrombosis. But also some of the anti-cancer therapies themselves. Some of them have off-target effects that in and of themselves increase the risk for thrombosis. And in addition, we have more frequent scanning to check for response to tumor or surveillance for recurrence and wider use of central venous access catheters. So our cancer patients' risk of thrombosis has been actually been increasing.

Patients with cancer-associated thrombosis can also have multiple different types of thrombosis. For the most part, our discussion today is going to focus on patients with cancer-associated venous thrombosis, as that's where we have much of the data or most of the data about how to manage these patients.

The last bit of information to set the stage is that the mechanisms of thrombosis are different in patients with cancer. And so we're all familiar with Virchow's triad, which is the 3 factors that contribute to the development in thrombosis in any patient. This includes stasis, vessel wall injury, and hypercoagulability, and that is true whether you're a post-op patient, the man on the street without cancer, or you're a cancer patient. But in particular aspects of being a patient with cancer increase your risk. Venous stasis, patients who have malignancy often have more prolonged bedrest and immobility. But we also can see that certain types of tumors can actually compress blood vessels, decreasing the blood flow, and leading to stasis.

The hypercoagulability component of Virchow's triad is significant in patients with cancer. There are procoagulant effects directly associated with tumors, there are tumor cytokines, recent major surgery. And as I mentioned before, chemotherapy, hormonal therapies and targeted therapies actually appear to have an increased risk of thrombosis associated with them. Endothelial injury occurs either by direct invasion from a tumor. Many of the chemotherapy agents will damage or result in dysfunctional endothelium. Again, the tumors themselves can release cytokines or induce the patient to produce cytokines, all which can trigger thrombosis. Central venous catheters, chemotherapy drugs and radiation therapy can actually contribute.

And so in the next part of our discussion, we're going to touch on current treatments for patients primarily with venous thrombosis. Alok, can you give us an overview of the current treatment options and what the guidelines might say?

Dr Khorana: Thanks, Jean. As you've already discussed, there's been a lot greater burden of cancer-associated venous thromboembolism. And what follows from that has been there's been a lot of more investigation into cancer patients who've developed acute venous thromboembolism and how best to manage it. I'm dating myself, but I've been around long enough to remember the warfarin era. That used to be the primary choice of treatment with vitamin K antagonists. And it still is a choice for some patients, specifically with the resourcing issues or in settings where resources are an issue.

And the challenge with vitamin K antagonist is the need to monitor INRs. I treat patients with gastrointestinal (GI) cancers and almost every single of one of my patients is on 5-fluorouracil, which has a lot of interactions with warfarin and so the INR's very hard to control in patients receiving GI cancer regimens like FOLFOX or FOLFIRI. And in general, INRs are hard to control in the cancer population with nutrition issues and so on. But that's definitely... Historically, has been the option that's been around the longest.

Next, there was the era of low molecular weight heparin (LMWH) monotherapy, which started with the presentation of the CLOT trial in the early 2000s and persisted for about a decade and a half as the... Really the only recommended guideline standard of for at least the first 6 months of treatment after acute VTE in a patient with cancer, effective in reducing the risk of recurrent VTE compared to warfarin as much concern for bleeding, but not quite as convenient as one would wish it to be. You get away with not having to do the INRs, but you're stuck with having to do daily self-injections for prolonged periods of time, not just for a week or 2, but for several months.

And in many countries, including the United States and Canada, cost is a real issue with LMWHs. And even as we transition to generic versions of LMHWs, loss remains an issue even with the generic version, and so that's been a big barrier for adherence and compliance with this class of drugs.

And last but not least, the last several years I've seen the advent of multiple direct oral anticoagulants (DOACs). These include drugs like rivaroxaban, apixaban, edoxaban that have overcome some of these issues related to treatment of acute cancer-associated VTE. They don't require monitoring with INR. They don't need daily self-injections. In that way, they're more convenient. They're expensive, but not quite as expensive as LMWHs.

But they have their own set of drug/drug interactions and there's real concerns about mucosal bleeding. Again, in the GI cancer population, there's concerns about GI bleeding, particularly with upper GI cancer such as esophageal or gastric cancer leading to major bleeding in some trials of some of these agents.

So the guidelines in current oncology reflects this nuanced understanding of treatment options. Thankfully, we do have treatment options and we've been able to move away from the one size fits all where it used to be warfarin for everybody and then it goes LMWH for everybody. And now we do have choices. And the guidelines essentially, whether you look at the oncology guidelines like ASCO or the hematology guidelines that like ASH or ISTH or ITAC, generally reflect the individualization of treatment.

So for many patients in whom there's no drug/drug interaction and oral intake is not an issue, you can start with a direct oral anticoagulant and you can stay on that for at least 6 months. The duration's still a little bit up in the air for patients with active cancer. We continue indefinitely for patients who are in remission. And off anti-cancer therapy, we generally would stop at 6 months. But for patients in home, there's concern about GI bleeding. Guidelines are still recommending consideration of LMWH or the DOACs.

Again, individualization and risk-benefit by patient is important in this situation, so it's not a one size fits all approach. And then finally, we still continue to use warfarin in patients in whom the other 2 options are not as easily available depending on the setting or resource issues. So a more nuanced understanding of treatment options, but more treatment options (available), still not the perfect option of the drug, which prevents recurrent VTE to a very large degree and doesn't increase the risk of major bleeding. And that's really the holy grail of anticoagulation in this setting.

Dr Connors: Jeff, is there anything you want to add to that?

Dr Weitz: Yeah. There are a few points to make. I think that's an excellent summary of the progression we've had in our options for treatment of cancer-associated VTE, starting first from with vitamin K antagonist like warfarin, then moving to LMWH, and now to the DOACs. Predominantly with apixaban and rivaroxaban because you don't have to bridge them with heparin, but also with edoxaban for people who've had at least a 5-day course of treatment with LMWH to begin with, or for those who have been on LMWH and are now switching to a DOAC.

So just a couple of points that are of interest, I think for this unique population. One is that every patient we have to assess benefit versus risk of the various treatments. And one other point to make is that there are some other considerations besides just the site of the tumor. We also have to think about the risk of thrombocytopenia with the treatments that they're getting. And that's particularly important for the sorts of patients that you and I see, Jean with hematologic malignancies where we know their platelet count is going to go down. We have no data about the safety with the DOAC with platelet counts below 50,000 platelets/µL. In the apixaban, the large apixaban CARAVAGGIO study, they used a cutoff of 75,000 platelets/µL for the platelet counts.

So often we'll have patients who need to... Even if we elect to put them on a DOAC, we might need to transition them to a LMWH or to nothing if their platelet count falls and then put them back on the DOAC when the platelet count comes back up. And we might have patients with GI malignancies who do very well on LMWH to start. And then if they're doing so well and not having bleeding on LMWH, they might ask or we might consider switching them over to a DOAC to get around this need for daily subcutaneous injections. It's definitely not one size fits all in these patients and sometimes it's a combined use will transition them from a DOAC to LMWH and back to a DOAC or from LMWH to a DOAC, depending on the particular concerns with that patient.

And I guess the other point to make is that there are patients who will come in with cancer-associated VTE who are bleeding, we have to determine how to manage those patients. And there are those who have brain metastases that are at high risk for bleeding where we might want to stabilize the brain metastases with radiation. Or we might even consider even with radiation, stabilization, such as... I'm sure you've seen this ... some because the patients say with metastatic melanoma with a lot of brain involvement, multiple, multiple cerebral metastases, some of which may already have blood associated with them. Those patients, it's really problematic to manage their anticoagulant therapy.

Dr Connors: No ...

Dr Weitz: Lots of things to consider.

Dr Connor:

Yeah, I think that is so true, Jeff. You've just described... Most of my day job in my role as Dana-Farber anticoagulation management service director, we have 2 pharmacists, a nurse and a nurse practitioner who a medical oncologist like Alok can refer their patients to us and then we monitor them. And the team is actually very good at following the platelet count, following the creatinine, swapping back and forth between LMWH and DOAC depending on bleeding risk, platelet counts. And as you said, brain metastases are really an area where we have anxiety. And even if they're treated, we also see... I just saw somebody yesterday who had stem cell transplant for MDSAML, had subdural hematoma, but he has a large proximal DVTT in PE. And how do you balance some of that? I think our current choice of anticoagulants still are not optimal for many of these patients.

I don't know, Alok, is there anything else you would like to add about how to choose between LMWH versus a DOAC? I know in our group, if we have people, and your patients might experience this, with lots of nausea, vomiting, and diarrhea. We will often take them off a DOAC and transition to LMWH until that clears up.

Dr Khorana: Yeah, and I think again, individualization is really key here. And I think that actually includes also assessing what the patients are... It has to be shared decision making because it's easy for us to say, "Well, this is the best trial and these are the best data, and therefore this is the drug you should take." But the best trial with the best data doesn't mean a thing if you write the prescription and you send the patient home with it and then they're not taking the drug. It's like those compression stockings that hang over the side of the bed. It's great that they're there, but they're not doing anything to prevent a VTE.

And we found... We and others have found that this adherence or compliance or persistence with drugs is a real issue in cancer patients. And this is surprising to me as an oncologist because cancer patients are amongst the most dedicated patients they are. They're very much in charge of their own care. They're dealing with very serious illness. But even in this population, specifically for LMWHs, we found almost 70% of patients who were prescribed LMWH ended up not being on anything.

And I think these are missed opportunities where if we sit down with patients and discuss with them what their concerns are, it may be cost concerns, it may be the inconvenience of daily self-injection in a population that has a very heavy burden of illness, cancer on top of the VTE or whether it's not having somebody at home to inject them. There's a myriad of reasons why patients may not be able to be compliant or adhere to the prescriptions we are providing them. But we have to have that discussion and that has to be shared decision making as we individualize these decisions for each patient.

Dr Connors: And these are excellent points and highlight the obstacles that we all face when caring for these patients. And then, look, I think it's interesting your data that show the significant drop off in adherence, whether it's that we're not educating patients about VTE, but quite honestly what I've seen is that patients are just overwhelmed sometimes. They're overwhelmed with the burden of following through their cancer treatments and treating the VTE often seems to take second, and rightfully so, a second in their whole scheme of what they can cope with. And so I think there are many reasons. But what I do think certainly your data show that LMWH and adherence to injections is really daily, once or twice daily injections is a big burden.

Many patients, even if that's the right drug for them and have some outpatient cost issues associated with that. So I think we've highlighted not only the environmental aspects of difficulty with anticoagulation.

But we also know from the data, from the large phase 3 RCTs, from meta-analysis that we still, even with the DOACs, have a high risk of bleeding in these patients and that there's certainly room to move in terms of improving care for our patients who have VTE.

And so Jeff, I'm going to turn to you now and ask if you can give us a hint of the future and what you think about new antithrombotic opportunities that are on the horizon?

Dr Weitz: Well, I think as you point out, there's no patient population that is at higher risk for bleeding than the cancer population. And so we are looking for safer anticoagulants, as particularly say for anticoagulants for those cancer patients who are at high risk for bleeding, such as those with upper GI malignancies like gastro-esophageal cancer. Those with genitourinary cancers, those patients are at particularly high risk for bleeding. So where can we go to get safer anticoagulants? What targets can we look at?

As you know, the current anticoagulants, whether we're talking about LMWH, which primarily works by catalyzing antithrombin inhibition of factor Xa and thrombin, and warfarin that works by reducing the potential for thrombin generation by lowering, in particular, the levels of factor X prothrombin.

They really are targeting the common pathway of coagulation, targeting the generation of factor Xa and the subsequent generation of thrombin. And if you do that, because that is the final mechanism for both thrombosis and for hemostasis, you're going to compromise safety.

But if we move upstream in the intrinsic pathway of coagulation and target either factor XII or factor XI, we may be able to disassociate the effects on thrombosis from those on hemostasis. And the idea he here is right now most of the new drugs are targeting factor XI because we have mounting evidence that factor XI plays a critical role in thrombosis, but is mostly dispensable for hemostasis.

So for hemostasis, which is the stopping of bleeding, is predominantly an extravascular event because you form a hemostatic plug to seal a leak in the blood vessel and it's triggered by the high concentrations of tissue factor that's in that hemostatic envelope that surrounds the blood vessel. And for that process, you really don't need factor XI in most cases. But for thrombosis, which is triggered by smaller concentrations of tissue factor in the arterial side, we think about the rupture of the atherosclerotic plaque. In the venous side, we think about monocyte macrophages that have been activated by cytokines to express tissue factor. We think about the damaged endothelium. In those situations, what happens is you get a little bit of thrombin generation and that thrombin feeds back. And one of the feedback loops is to activate factor XI to promote thrombin generation and induce thrombus propagation and growth. So by inhibiting factor XI, we can block that process, and we can do it without much of an effect, we hope, on hemostasis.

So there is a lot of interest right now on factor XI inhibitors, and these come in different classes, we have agents like fesomersen, which reduce the hepatic synthesis of factor XI, thereby in reducing the amount of factor XI available to promote thrombosis through this amplification loop. We have antibodies that bind to factor XI, or bind to factor XIa and block its activity. And we have small molecules, very much like the DOACs that bind to the active site of factor XIa in a reversible manner and prevent it from doing its job of propagating coagulation. So these agents are now in clinical trials. The small molecules are being evaluated for stroke prevention in patients with atrial fibrillation, for secondary stroke prevention in patients with non-cardioembolic stroke, for patients with acute coronary syndrome.

And one of the antibodies, abelacimab, binds to factor XI zymogen and blocks its capacity to get activated by either factor XIIa or by thrombin. The first dose is given intravenously to get a rapid effect, but after that it's given subcutaneously once a month. So for that adherence issue that Alok talked about with LMWH, which has to be given by subcutaneous injection every day, and in some people twice a day, we can dial that out. The other thing is that we're still stuck with our cancer patients with poor renal function. They may come in because they already have chronic kidney disease or some of their treatments might result in acute kidney injury. And that's not a problem with abelacimab.

So you have those advantages of convenience of one monthly dosing, which is better than taking a tablet once or twice a day or taking an injection once or twice a day, and you can dial out the drug/drug interactions and dial out the renal clearance issues. So there are some other potential benefits of this approach.

It's being investigated in patients with cancer-associated venous thromboembolism, just the sorts of patients that we've been talking about in 2 trials. One, the ASTER trial is comparing abelacimab with apixaban in patients with cancer-associated VTE who are candidates for a DOAC. And the other trial is... MAGNOLIA trial is comparing abelacimab with dalteparin, a LMWH, in cancer patients who are considered to be better candidates because of the risk of bleeding for a low molecular weight heparin than for a DOAC. So those 2 trials together will give us lots of information about both the efficacy and safety of a factor XI- directed approach versus our current approaches of using either a DOAC or a LMWH in our cancer population.

Dr Connors: So Jeff, it's very interesting the use of abelacimab and the new trials in patients who have cancer-associated thrombosis. I think these are going to address significant questions. And I hate to use this term, but the unmet need for these patients, which is really reducing the bleeding risk without sacrificing efficacy. But what about some of the other patient populations for whom these drugs might be of benefit? Those as we've briefly mentioned, renal insufficiency, atrial fibrillation, other cardiac situations that me as hematologist doesn't really see every day? Can you comment on the broader application for factor XI inhibitor use?

Dr Weitz: Sure. Well, in addition to the studies in cancer-associated venous thromboembolism, abelacimab is also being compared with rivaroxaban in a phase 2 study in patients with atrial fibrillation. And a phase 3 study, the LILAC study, comparing abelacimab with, essentially with placebo or with aspirin in patients with atrial fibrillation who are considered not to be candidates for a DOAC or for warfarin is also underway. And of course, we're going to not only have antibodies, but we've got small molecules. We've got milvexian and asundexian, which are small molecule inhibitors of factor XIa that are given orally. And these agents are both starting in phase 3 trials. Asundexian is being compared with apixaban in patients with atrial fibrillation, and it's also being compared with placebo on top of antiplatelet therapy for secondary stroke prevention in patients with non-cardioembolic stroke.

And remember, that non-cardioembolic stroke is a place where the DOACs feared to tread because of the risk of bleeding and hemorrhagic transformation. And yet here we are with the factor XIa inhibitors in that space. With milvexian, 3 phase 3 trials are underway or we will start soon. One again, comparing milvexian with apixaban in patients with atrial fibrillation. Another comparing milvexian with placebo on top of antiplatelet therapy for secondary stroke prevention. And a third trial in patients with acute coronary syndrome, looking not only at the short-term, but extended treatment with milvexian versus placebo on top of a changing anti-platelet regimen that might start with dual anti-platelet therapy and then might transition to single anti-platelet therapy over time to try and prevent recurrent major adverse vascular events.

So lots of action on the factor XI space. And finally we'll have the results of 2 phase 2 trials, both of which are completed in patients with end stage kidney disease on dialysis. One trial with fesomersen, a factor XI directed antisense oligonucleotide that reduces the synthesis of factor XI and the other with xisomab, the antibody against factor XIa. And both of these trials that haven't yet been... Results haven't been published, but both show the incredible safety of factor XI inhibition in this very vulnerable patient population who are particularly prone to bleeding. And these agents have been given on top of the heparin that they get for dialysis, and they're showing improvement, clotting events on the dialysis circuitry.

So it, again, suggests that maybe the factor XI inhibitors will also be good for prevention of device associated clotting. And in our cancer patients, that device associated clotting includes those central venous catheters that we use for venous access and for delivery of chemotherapy and other devices like even mechanical heart valves, a place where we can't use DOACs right now might be a place where the factor XI inhibitors might shine. So we have a lot going on and a lot of interesting results still to find out.

Dr Connors: I'm looking forward to this. I like, Alok, have been in my field for a long time. The DOACs revolutionized our care for these patients and for their quality of life. It sounds like these factor XI inhibitors hold even greater promise with not only improving quality of life, but actually decreasing risks associated with anticoagulation. Fascinating forward progress. Alok?

Dr Khorana: Because this program's been focused primarily on venous thromboembolism, one of the things I'm looking forward to is the impact on arterial events, which are also quite substantial in the cancer population. Because venous events are so much more common, we forget about the arterial events. But there's not any other population that has a rate of 3%, 5% at 6 months of stroke and MI, including with newer agents like, immune checkpoint inhibitor therapy or multi-targeted tyrosine kinase inhibitor therapies, like sorafenib or sunitinib, all of which have been documented to have an increased risk of arterial events. And so the possibility that this new class of drugs holds for preventing not just venous events, but also arterial events, I think is fascinating. It adds to the potential for benefit as the field moves forward.

Dr Connors: That's an excellent point and I think that that's something that frustrates my anti-coag staff at the Dana-Farber, frequently, because although VTE is much more commonly encountered, the arterial events are more concerning and often more difficult to manage and we do not have great strategies for that right now in our cancer population.

Dr Connors: Certainly, exciting advances. Although DOACs are certainly non-inferior to LMWH in many situations, as we've discussed, they have a higher risk of bleeding. And that is really where we hope that these trials will show us similar efficacy, but even improved safety above both LMWH and DOACs. I think that this is, again, promising. I'm glad to see these trials off the ground.

Dr Khorana: I think it's important as we've discussed today, to state that overall the field has evolved to a great degree in the last 10 or 20 years, and in a way that's been very beneficial for patients. We've gone from these one size fits all approaches to having the ability to individualize treatment and to able to pick drugs that if you have a drug/drug interaction, for instance with warfarin or with a DOAC, then you could go to a different class of agents like the LMWHs. And the bad outcomes that we worry about in cancer patients, recurrent VTE bleeding have started to diminish, but the job's not done yet. I think bleeding still remains paradoxically an issue in this hypercoagulable state. And so the new class of drugs that are on the horizon that Jeff so eloquently described, I think hold a great deal of promise and hopefully will move the field even further forward.

Dr Connors: So Jeff and Alok, I'd like to thank you for this great discussion. I'd like to thank our audience for participating in this activity and we encourage you to please continue on to answer the questions that follow this presentation. We want to thank you for your attention.

This transcript has not been copyedited.