BTK Inhibitors: Infections and Secondary Malignancies

Harry P. Erba, MD, PhD:OK, now a toxicity we haven’t spoken of yet—infection—especially on the data that came from CNS [central nervous system] lymphoma with the combination of ibrutinib and steroids. Do you want to tell us more about that?

Anthony R. Mato, MD, MSCE:Yes. So there was a signal. First of all, with all of these targeted agents, we don’t have a great understanding of how they inhibit the function of the immune system. And unfortunately, it’s not simple like, “I’m going to check a CD4 count or an IgG [immunoglobulin G] level as a predictor of adverse events from opportunistic infections.” There’s been this ongoing history of these drugs, for example, idelalisib, which had major issues with CMV [cytomegalovirus] reactivation and PCP [pneumocystis pneumonia]. With ibrutinib, particularly when given in combination for these heavily pretreated patients that you mentioned already, in the CNS lymphoma patients there’s invasive aspergillosis, which was an issue. Also, PCP has been reported to be associated with ibrutinib. There was aBloodpaper from the NCI [National Cancer Institute] that talked about that as well.

I think the standard of care right now is not to provide prophylaxis for these infections, with a low threshold to do so if you feel that that patient may be at increased risk, keeping in mind that you can’t really give a prophylaxis for invasive aspergillosis because there’s a CYP3A4 interaction between most of the drugs that are out there, at least the ones that are oral, and ibrutinib. And so that is a major problem that is not easily overcome, if you want patients to be treated in the outpatient setting and not come in for infusions for a very rare event.

We think that these drugs probably inhibit more function than numbers, and that becomes hard to predict. So any time somebody coughs or there’s any reason to suspect something that could be opportunistic, we admit them, we do a bronchoscopy, we biopsy, we look, because we do sometimes find these things.

Harry P. Erba, MD, PhD:Yes. I recently ran into this. My own patient showed up with cold agglutinin disease, a warm antibody hemolytic anemia, with a hemoglobin of 4 that required steroids, with a white count of 200,000 from CLL [chronic lymphocytic leukemia], and a RAI stage III disease, and needed treatment with steroids and ibrutinib. It’s quite challenging figuring out what to do there, especially in the area of the country where I’m practicing. I see a lot of aspergillus infections, especially in my acute leukemia patients. So not a lot of…

Anthony R. Mato, MD, MSCE:So not a lot of prophylaxis. Well, for mold I don’t think you can, but at least with the steroids I would give a prophylaxis for PCP.

Harry P. Erba, MD, PhD:We’ve talked about ibrutinib. How about acalabrutinib? How does it compare? You mentioned something about that earlier.

Anthony R. Mato, MD, MSCE:I think the AEs [adverse events] are similar, but maybe less. We don’t know for sure yet. I think that many people in the community are hesitant to speculate that they’re less, especially given the fact that we have head-to-head data that will come out in the next year or two. It’s just hard to judge one drug versus another. I feel like you do one or the other a disservice by making that comparison. So I tell patients what the AEs were in the individual trials, but I oftentimes don’t get into putting the 2 tables next to one another and saying, “Hey, we’re getting less AF [atrial fibrillation]. We’re getting less…” Fortunately, the makers of acalabrutinib and zanubrutinib were courageous enough to challenge ibrutinib head-to-head. So we will have those data sometime.

Harry P. Erba, MD, PhD:In CLL, we know that these patients are at higher risk of epithelial carcinomas, skin cancers. Personally, I often send my patients to a dermatologist once or twice a year for surveillance. With the BTK [Bruton tyrosine kinase] inhibitors, is there any special signal for an increased risk of those carcinomas?

Anthony R. Mato, MD, MSCE:I don’t think so. I think that the best data that we have are the randomized trials. We have ibrutinib versus antibody. We have ibrutinib versus chlorambucil. We have ibrutinib versus FCR [fludarabine/cyclophosphamide/rituximab]. There have been several randomized trials conducted. I haven’t seen a strong signal of secondary malignancies favoring the ibrutinib arm or transformation favoring the ibrutinib or the BTK arm. So I think everybody has these anecdotal stories of these drugs that we start on their seventh line of therapy and then they transform. But when you look apples-to-apples comparisons across randomized trials, that doesn’t really bear out as much.

Harry P. Erba, MD, PhD:We know that with FCR [fludarabine/cyclophosphamide/rituximab], or fludarabine, Cytoxan-based regimens, there is a higher risk of….

Anthony R. Mato, MD, MSCE:Marrow failure.

Harry P. Erba, MD, PhD:Marrow failure, MDS [myelodysplastic syndrome]. Have we seen that with the BTK inhibitors?

Anthony R. Mato, MD, MSCE:I don’t think I’ve seen a signal. If it exists, I haven’t seen a signal that suggests that it’s causing those types of secondary malignancies.

Transcript edited for clarity.