Transcript:Ruben A. Mesa, MD, FACP: Rafael, clearly there’s a lot of guidance out there to try to help with giving guidance, and I do tend to agree with Elias that there’s really nothing standard about AML therapy and that it really needs people who have a strong focus. In terms of guidelines, any of those that you have found that are helpful that you see folks are using in the community?
Rafael Bejar MD, PhD: In terms of AML therapy?
Ruben A. Mesa, MD, FACP: In terms of prophylaxis. So in terms of infection prevention, dealing with neutropenic fever, NCCN Guidelines, other things; things that you’ve seen that folks have found helpful.
Rafael Bejar MD, PhD: I think the NCCN Guidelines are a great example of where actually putting on paper a standard treatment regimen is helpful, so that groups that don’t have as much experience can rely on the experience of others to help. But to Elias’s point, I think as good as the individual physician may be, the real important thing is to have the entire treatment team have experience with treating these disorders, having the ER know to start antibiotics on time, having the nurses know how to recognize patients who might be ill and need more attention. That all comes into play. But things like, I think you mentioned the NCCN Guidelines are useful. The IDSA also has guidelines about treatment of neutropenic fever, when to add certain antibiotics and when not to overtreat, and when not to use MRSA treatment, for example, for prolonged periods of time and so on.
Ruben A. Mesa, MD, FACP: So, as we’re thinking about specific agents in the preventative setting, is there a typical recipe that your institutions would use in terms of a particular azole for prevention? Or antibiotic or antiviral? Does everyone get one of each in terms of a triple therapy?
Elias Jabbour, MD: Well, the policy at our institution, we use quinolones for bacterias. We give valaciclovir for covering viral, and then azoles, essentially because azoles are orals to be given. Otherwise, you have to give them IVs, come back, and it’s complicated. The choice of azoles? Posaconazole has a preventive labeling, which voriconazole, the new one, doesn’t have so far. But we have phase II studies assessing these drugs. But one should keep in mind that there’s an absorption problem. You have to check for the level and then the co-pay. When I write a prescription or my pharmacy writes a prescription, the patient will call me, ‘My co-pay is $500 per month or $1000.” Then fluconazole? Yes. By default, I have to give them something. So, that is still not so easy. At Anderson, my pharmacist, as Rafael mentioned, we have a team. So, the pharmacist will call the social worker, case manager, and get some help, and call pharma to see what we can help our patient with. But it’s still a struggle. And if you don’t have coverage, or home care, or something, they have to come back to the hospital and we move them to IV drugs like caspofungin or the liposomal formulation Ambisome and others.
Ruben A. Mesa, MD, FACP: As you say, we have a strong armamentarium. The posaconazole preventative data were very strong, but clearly things need to be individualized. Patients are on complex regimens, and clearly coverage remains a complex issue. I surely hope for my patients that it simplifies over time. It’s very disappointing when we clearly have effective therapies, preventions, antifungals, or other options, that we’re limited in that way.
Rami Komrokji, MD: I think, to your point, is that sometimes the toxicity profile for all those medications, or the course, can dictate some of them. For example, in our institution, the first few days when the patients are on anthracycline regimen, they start with micafungin to avoid the interaction. Once they finish the third day, then they will shift to an azole. Posaconazole may have less transaminitis than voriconazole. So the toxicity you see. And where are you in the regimen in transplant? Obviously, in patients who are immunosuppressed, since there are so many interactions, that sometimes dictates the choice. But I think the data on prevention are clear that posaconazole and voriconazole are better than fluconazole for sure.
Ruben A. Mesa, MD, FACP: Now, what about length of therapy? If someone is on a preventative medicine or preventative antifungal, how long would you keep that therapy on board?
Rafael Bejar MD, PhD: It partly depends on what’s coming next in that patient’s future. So if the patient really is headed to transplant, we know that they’re going to get to a point where they’re going to be immunocompromised severely even if they’re not at that very moment. So, we typically continue the prophylaxis through that experience. In general, if you have a patient who is just going to get high-dose ara-C consolidation and they’re done with that process, recovery of counts is a good point to assess where they’re at.
Ruben A. Mesa, MD, FACP: It’s very tricky. Certainly, as I try to think about people recovering, I think the immune system recovering is really a slow process, as well as recovery of all the subtle injuries they receive through the therapy, the mucositis and things of that nature. I agree with you, as well. Particularly, with antifungals, it tends to be a much longer course, particularly since there’s usually something on the other end as opposed to it being the final cycles of consolidation. In particular, if they’ve had an infection, we’ll continue to try to suppress it. In my area, we, as well, have a lot of cocci and other factors that we clearly have to be mindful of.
Elias Jabbour, MD: Among the azoles choice, as well, it could be what you’re doing. For example, if I’m giving clofarabine for AML induction, I have liver dysfunction. Or in ALL, giving the new monoclonal antibodies, inotuzumab ozogamicin, can cause liver dysfunction. I maybe limit the azole choice I have. Some of them cause QT prolongation, some of them don’t cause QT prolongation. So, beyond the label of preventive or not, you may make different choices based on what you’re doing for a specific patient.
Ruben A. Mesa, MD, FACP: As we look at individualized medicine, I think that part two will evolve. I think we’ll have a better sense of predisposition to infection. There is a great assessment of the microbiome and other factors, as well as probably a much better understanding around the metabolism of some of these agents on an individual level. Because, again, I think with dosing and some of the drug interactions, it’s still a little bit uniform dosing. But I think we’ll certainly have some refinement.
Rami Komrokji, MD: I think one thing we didn’t touch on is the challenge in diagnosing invasive fungal infection. Most of the time, we treat for a presumptive infection, because in the setting of AML, to do bronchoscopy sometimes is not feasible, imaging. Patients are immunocompromised. They have neutropenia. They may not have the classical features. So I think it’s a key to recognize that those patients are at high risk for fungal infections, and sometimes it’s absolutely okay to treat as a presumptive infection without absolute evidence of infection because sometimes it’s difficult to do that.
Ruben A. Mesa, MD, FACP: I think you raise an excellent point: that prevention is so key in this setting. As I still look at the arc of AML as a whole, many of these patients still rely on an allogeneic transplant as a key part of their salvage, or a cure. Nothing can really derail that process more effectively than an invasive fungal infection that has not responded or is progressing. Patients lose the opportunity for some of those options or the option of going on a trial or other things because they have a very severe infection. So, nipping those things in the bud is really essential because otherwise then we just have the mortality, not only from the disease, but really from the infectious causes that are related.
Ruben A. Mesa, MD, FACP: Shifting gears back again, we had been taking the deeper guide regarding the azoles and their potential role, both in prophylaxis and in treatment. And, as we know, there are four azoles at the moment. There’s fluconazole, there’s voriconazole, there’s posaconazole, and there’s isavuconazole. Now, Rafael, as we’re thinking between these, what are the different things you’re thinking about as you’re utilizing an azole in terms of optimizing the care?
Rafael Bejar MD, PhD: I think about the coverage that each one of them has. So fluconazole is very good against Candida species and things like that, but not so effective against the molds. And we talked about how that’s important in preventing infections in patients, in particular, who have a very high risk of these infections. So that influences my decision. The toxicity of the medications, what organ functions they affect, is also going to be a key component. Does the patient have hepatic compromise, or are they likely to, based on the treatments that we’re giving? And then finally, what are the drug-drug interactions that are going to influence my decision? So, for example, you mentioned that in patients on clofarabine where you expect hepatic toxicity, you might want to avoid voriconazole where it’s known to cause a greater degree of transaminitis and use an alternative agent.
And patients who may have QT prolongation as a known consequence of one of the azole treatments, especially if given in combination with another drug that can do that as well, you may want to take that into account. So, those are the features that we consider when we think about which drug to use. But, in actuality, we rely on the judgment and interactions with our ID colleagues who have a tremendous amount of experience with these agents, and together we come up with a plan.
Elias Jabbour, MD: I think the more options we have, the better the outcomes. So, at least we can personalize. Even with an antifungal therapy, as Rafael mentioned, in somebody who cannot take oral medicine, what do you do? Somebody who is on a specific chemotherapy, what do you do? Somebody who has QT already prolongated, what do you do? So at least with the plethora of agents we have today, we can select which one is the best. And, again, we rely on our ID [infectious disease] colleagues’ recommendation to do what’s best for the patient.
Ruben A. Mesa, MD, FACP: As well as being guided by the evidence as best we can. I know for mine, I really view that prevention role as very slightly different from where we have an active infection where we’ve been guided in such. I certainly was very impressed by the 2007 New England Journal of Medicine article, the role of posaconazole compared to fluconazole and voriconazole was very strong. All things being equal, I certainly consider that a strong option. But we need to weigh all of these different components as part of that.
Transcript Edited for Clarity