IBD Drive Time: Jordan Axelrad, MD, on IBD and Malignancy

Dr Jordan Axelrad and host Dr Raymond Cross discuss the considerations for IBD treatment among patients with history of or a newly-diagnosed malignancy, including when to switch IBD treatments the importance of controlling disease, and how to manage checkpoint inhibitor colitis.

Raymond Cross, MD, is director of the IBD Center at Mercy Medical Center in Baltimore, Maryland, and professor of medicine at the University of Maryland. Jordan Axelrad, MD, MPH, is codirector of the Inflammatory Bowel Disease Center at NYU Langone Health.

TRANSCRIPT:

Welcome, everyone, to IBD Drive Time. I'm Raymond Cross from Mercy Medical Center, and I'm delighted to have my friend, Jordan Axelrad from NYU, here as a return guest to IBD Drive Time to talk about malignancy and IBD. Jordan, welcome back to IBD Drive Time.

Thanks, Ray.

So let's, for the listeners, one of the things I think about, Jordan, as I'm getting older, my patients are getting older with me and these issues like malignancy do come up more frequently as your patients age with you. So which of our meds specifically are associated with malignancy in IBD?

Dr Axelrad; So certain cancers are seen more commonly in patients with IBD who take particular medications. So for thiopurines and immumodulators, there have been cases of nonmelanoma skin cancers, lymphoma, and genitourinary cancers, as well. For patients on anti-TNF, there have been cases of melanoma, and if combined with thiopurines nonmelanoma skin cancers and lymphoma.

There are limited data in folks with rheumatoid arthritis suggesting a link between JAK inhibitors with nonmelanoma skin cancers and even lung cancer and lymphoma as well. Current evidence, though, doesn’t show any increased risk of malignancy in patients with IBD treated with essentially all our other agents—vedolizumab, ustekinumab, risankizumab, mirikizumab, ozanimod, and etrasimod—although truthfully long-term data are really lacking on these other drugs. But the ones we mentioned are where we have the most evidence and the most data for a link.

Dr Cross: I just want to follow up on 2 things, Jordan. You're the expert on this, but methotrexate, my understanding of methotrexate is, small increased risk of nonmelanoma skin cancer based on some RA data, but no link with lymphoma. Am I remembering that correctly?

Dr Axelrad: Yes. So of the immunomodulators, methotrexate has really only demonstrated a link with nonmelanoma skin cancer. Again, data are very limited, mostly from outside of IBD, and no particular link with lymphoma. So primarily, our major problem of increased risk of cancers is really related to thiopurines.

Dr Cross: And with the JAKs, pretty clear link with nonmelanoma skin cancer, I think, and possibly lymphoma, although the cases are quite small. The data from ORAL surveillance in that unique RA population that they studied, my understanding there was that the cancer risk seemed to be linked to patients that were older and/or that had a history of smoking. If you were under 65 and didn't smoke, there was no increased risk of cancer in that population.

Dr Axelrad: Exactly. So thus far, data in patients with IBD have actually not suggested an increased risk of malignancy in those treated with JAK inhibitors. But you're right, in older patients with RA, with other comorbidities, there was this link with specifically nonmelanoma skin cancer, but also some cases of lung cancer and lymphoma. There have been a couple of other meta-analyses and pooled analysis of clinical trial and long-term extension data. These too have sometimes demonstrated conflicting results, but at least in the IBD population, we really have not seen a signal for increased malignancy risk.

Dr Cross: And, you know, there was a lot of discussion about JAK selectivity and for efficacy of therapy and then potentially for safety. In my interpretation of the trial data is that the JAK 1 selectivity for safety really doesn't make much of a difference. And I don't think there's enough data for that for malignancy. What do you think about the selectivity? Does that make a difference for cancer risk?

Dr Axelrad; I don't think we have enough information, but I agree with you that I don't think that's clinically too relevant at this point. I think JAK inhibitors carry some other baggage that are probably more important for our patients with IBD. And I'm not sure the selectivity really modifies at least the cancer risk.

Dr Cross: So Jordan, let's say you have a patient in the office, man or woman, I don't think gender matters so much for this question, who is on a biologic or advanced therapy and was just diagnosed with a malignancy and is going to undergo treatment. How do you approach that or does it depend on what treatment they're being given?

Dr Axelrad: So you're right when we first started this, that our patients with IBD are getting older, where we are all getting older. Cancer is very common. Cancer becomes more common as we get older. But the reality of our current data are that very little is known about the impact of IBD and actually the IBD therapies on patients who develop an active cancer. And then specifically questions about cancer progression, we have even fewer data.

 So thus far, you know, essentially despite all this limited data, in patients with active cancers undergoing cancer treatment, our approach and my approach in particular is that if IBD needs to be controlled, we use IBD therapies as needed. And particularly that’s because you want your patient to be able to tolerate their cancer treatment. Now of course you’ll be chatting with oncologists and radiation oncologists and coordinating that, but probably the most important aspect of having cancer is getting that cancer adequately treated. And so if IBD is active, and that's interfering with the ability of a patient to tolerate cancer treatment, IBD needs to be treated and that needs to be addressed as you would any other patient, but of course in concert with the patient's oncologists and the onc team.

In terms of specific cancer treatments, there are some limited data showing that cytotoxic agents may have a beneficial effect on intestinal inflammation, whereas hormone deprivation therapies such as those given for breast or prostate cancers, alone or even in combination with cytotoxic agents, may increase the risk of flare.

Where we seem to have the most evidence is that for folks receiving immune checkpoint inhibitors, which are being used even more broadly in a variety of cancers, this definitely can increase the risk of IBD flare, and patients often require more aggressive IBD management in this setting.

So overall, my approach is if our patients develop cancer, I'm working with the onc team to make sure that patients have their IBD adequately treated so that they can get through their cancer treatment. And we use therapies as needed.

Dr Cross: So Jordan, my approach in a patient who's in a deep remission for their IBD, if they're undergoing systemic chemo for their malignancy, I've tended to hold their treatment. Now, do you agree with that approach? And then if they were perhaps considering a checkpoint inhibitor and they're not on an anti-TNF or anti-integrin, are you changing their therapy specifically to something that would work for checkpoint inhibitor colitis? I know it's a 2-part question and that stinks, but can you address that?

Dr Axelrad: Sure. So there are some specific instances where I'm making deliberate changes to the IBD therapy. So if a patient develops a thiopurine-related malignancy— nonmelanoma skin cancers that are recurrent and significant, lymphoma—I'm generally stopping the thiopurine. If a patient is on an anti-TNF therapy and they develop melanoma, I'm going to be stopping the anti-TNF.

Essentially, for all other types of cancer, that's where I'm really just looking at what's the status of the IBD and what's going to be the cancer treatment plan. So if patients are going to receive cytotoxic agents and they're in deep remission, I will generally hold their IBD therapy. If patients are going to be receiving immune checkpoint inhibitors, this is where I'm being very aggressive with the IBD therapy. So if they're already on an advanced therapy, a biologic or small molecule, I'm making sure they're in deep remission. If they're not, I'm escalating therapy to try to get them in as deep remission as possible and having a very intense monitoring during that treatment to ensure that patients don't flare and don't have interruptions to their cancer treatment.

Dr Cross: So I want to make sure I understand it. So someone who's going to get a checkpoint inhibitor, you don't care so much what IBD therapy they're on, as long as that IBD therapy is controlling their disease well. So you would just generally keep them on it with the checkpoint inhibitor. You wouldn't hold it.

Dr Axelrad: Yes. You would definitely keep them on it. We have the most data, as you mentioned, for vedolizumab and anti-TNF therapies, although truthfully all IBD therapies have efficacy in immune checkpoint inhibitor colitis, we just have the most evidence for our biologics, but the main point here is just patients really need to be in as much remission of their disease as possible so that they don't encounter a problem when they're on their checkpoint inhibitor therapy.

Dr Cross: And let's say this dreaded scenario occurs where a patient has a newly diagnosed cancer, a checkpoint inhibitor is recommended, their IBD is not under great control on whatever therapy they're on. My sense from what you said is you would change their IBD therapy while they're undergoing their cancer treatment. And in that situation, would you prefer an anti-TNF or vedo because there's the most data in that situation or does it not really matter?

Dr Axelrad: Yes. So I would definitely prefer in that setting to use where we have the most data. So a good example here is we have a patient who's got more moderate ulcerative colitis that's on mesalamine, maybe. We do a disease activity assessment before they're going to start a checkpoint inhibitor and they have some active disease. This is a good example of where I'm escalating therapy, where I likely add for vedolizumab. I think anti-TNF is very reasonable just because you really want to mitigate all the risks that patients are going to be subject to on a checkpoint inhibitor. We have a lot of data showing patients with IBD do poorly with checkpoint inhibitors, huge risks of flares. And so this is the time to be very aggressive with their IBD therapy.

Dr Cross: And this could be a whole checkpoint inhibitor talk or a podcast. But so are we going to get to a point here, Jordan, where we're giving an anti-integrin prophylactically while they're getting a checkpoint inhibitor? Is that where we're heading in the cancer space, do you think? I know asking you to put on your crystal ball?

Dr Axelard: So, well, the first thing is not all immune checkpoint inhibitors are created equal, right? So the most commonly used agents are cytotoxic T lymphocyte-associated protein 4, CTLA -4 drugs; programmed cell death protein, PD1drugs; and PDL-1 which are programmed death ligand-1 drugs. And these all have a variety of different targets and of course as we all know now have improved the outcomes of a variety of different cancers. And in combination these drugs seem to have the highest risk of toxicities—colitis is just one of many complications that these drugs can cause. And I agree that, to an extent, that for patients who are at risk who are going to be getting combinations of these immunotherapies, these are patients we may want to consider preventative colitis therapy, in particular, certainly for patients with IBD, they should be on a therapy because they're going to be at highest risk.

But for those receiving combination agents where risk of colitis is high, I think that could be considered, you know, in the future, especially something, you know, as safe as we intuit as an anti-integrin.

Dr Cross: Before I ask you about a couple of patients areas, I just want to remind the IBD Drive Time is sponsored by the AIBD network. And there is the final regional Advances in IBD for 2024 going to take place September 6th to September 7th in LA, and I will be speaking there. So looking forward to see our West Coast listeners attend that awesome meeting.

So, Jordan, I saw a patient this week who has a j-pouch, has de novo Crohn's of the pouch, had multiple draining perineal fistulas and needed synergistic treatment with infliximab and azathioprine. In fact, this is on alipurinol- azathioprine combo because he was a shunter who developed a new squamous cell cancer next to his left eye. It's very, very specific. So we had a long discussion about pros and cons of withdrawal of the thiopurine versus continuing. And he weighed recurrent perianal disease as being more concerning the recurrent squamous cell cancer. So what do you think about that situation? I think it's pretty rational. I told him, I think if you have another, then that maybe changes our conversation. But squames make me very nervous.

Dr Axelrad: Yeah, I agree. And even recurrent multiple basal cell carcinomas, which are less concerning, but can also be very disfiguring, patients will require, you know, removal of that, maybe Mohs surgery. So I agree completely. In that setting, I would have stopped the thiopurine and optimize that biologic by increasing the dose or frequency as needed to get to where they need to be. And that's really been my approach with all of the drugs that have been associated with nonmelanoma skin cancers. If there's multiple or recurrent, particularly the squamous cell carcinomas, I definitely favor discontinuation and utilizing another drug or optimizing whatever drug is their primary agent.

Dr Cross: Yeah, and I think that for the listeners, it may not be well known, but when you have one squamous cell cancer, your risk of your mortality is increased. So people, I think, generally consider skin cancer as being benign, but squamous cell cancers— Jordan, you mentioned the dermatologic complications of multiple basal cells—but squamous cell cancers actually increase your mortality risk so they’re not to be taken lightly for sure.

How about melanoma? Sometimes I think we worry more about melanoma in our treatments than dermatologists do, and perhaps oncologists. But you know, superficial melanoma in a patient that's on an anti-TNF, is that an absolute indication to stop the anti-TNF? Or I think, again, it comes back to shared decision-making. Probably depends on the severity of the disease, how difficult it was to put them into control, and so forth.

Dr Axelrad: That's a complicated question. I think we definitely have more concern about melanoma. I think many dermatologists do as well. A more superficial melanoma that can be removed surgically, that’s not going to require treatment, I think it’s a complicated situation. And yes, shared decision-making. For folks with very complicated IBD, perianal fistulizing disease, who really do better with anti-TNF on board, that’s a conversation. If it’s a patient who’s been in long-standing remission on an anti-TNF, that’s a candidate for another therapy, I probably choose another therapy in that setting, even if this was something that was not invasive, that was superficial from a melanoma standpoint. But I think with that cancer in particular, since if it recurs and is more advanced stage can be still quite devastating, depending on what the conversation is, the status of the IBD, that's really what would guide my decision-making.

Dr Cross: What about your patient that's had a cancer in the past? And maybe it's not the remote past. Let's say it's within 5 years. So what's the data say about the risk of recurrence with our therapies in that situation? So we talked about association with new cancers, but how about recurrence?

Dr Axelrad: Yeah. So the first thing are that patients with prior cancers are really not well represented in any of our clinical trials of IBD therapies. And so the data on the impact of meds on new or recurrent cancer and patients with a history of cancer are also very limited. So in the data that we have, some of which are prospective, some of which are from a registry that I'm involved in called SAPPHIRE, where we're specifically looking at the safety of immunosuppression in patients with IBD prospectively, thus far, we've seen that combining all cancers together, that it seems that our drugs, whatever you're choosing, don't seem to have an increased risk on new or recurrent cancers—although, again, these are small cohorts. Other data from Europe, from national health insurance databases have confirmed some of these similar findings. We have the most robust data for thiopurine and anti-TNF, but our emerging data have really confirmed that all our IBD therapies seem to be safe in those who have a history of cancer.

Now of course if you have someone with a recent lymphoma, within the past year, and you’re thinking what therapy am I going to use, they’re in remission, yeah, I’d probably avoid therapies associated with lymphoma, like a thiopurine. But for all other types of situations, I'm generally using the drug that patients need for their disease activity and severity. And again, we have some of this reassuring data, but they're from very small studies.

Dr Cross: And I think you and I practice similarly. In general, if the patient has more moderate symptoms and inflammatory burden and they're not that ill, no compelling EIM to dictate one way or the other, we're trying to pick the safest drug for them possible anyway, in general.

Dr Axelrad: And remember, cancer is something that is very significant. This is something patients ask us all the time when we’re starting a drug. Very often, they’re not asking us how well is this drug going to work for my IBD, how quickly am I going to feel better? Very often they ask is this drug going to give me cancer, is this drug going to give me an infection? So I think it’s really important that we're informed about what the real risks are and how to manage folks who do develop some of these complications.

Dr Cross: Yeah, 100%. And framing like risks, everyday risks, like risk of dying in a car accident with, you know, a 1 in 2500 risk of lymphoma often is very helpful for them. And although then they don't want to drive. So in New York City, they don't drive much anyway.

All right, Jordan, fun fact. Tell us something about yourself that the listeners may not know.

Dr Axelrad: So I can't remember if I ever mentioned this.

Dr Cross: I thought you told us about your vacation spot last time, your favorite vacation spot, if I remember right.

Dr Axelrad: Yeah, that sounds about right. But actually, in a corollary to that is that I'm pretty crazy about points. I don't know if I've ever mentioned this to you, that I don't I think I have used my own funds to pay for a flight except for taxes in a decade because over the years I've like really focused on how to use credit card points and get flights always covered. So I'm like coming for the points guy because I'm pretty sure I know how to get like the best redemptions and all of the airlines and everything. So I'm real crazy about that and I'm actually able to work that out pretty well.

So for example, we just came back from Southeast Asia, flights for free, things like that. So if you need any tips, I'm here for it.

Dr Cross: Jordan, I did not know that. And I know you pretty well. There's much I have to learn from me other than cancer and IBD— points, flights.

Jordan, this has been great. I learned a lot. I'm sure our listeners, this is very valuable. And we hope to have you back soon.

Dr Axelrad: Great, thanks, Ray.