Treating With BTK Inhibitors in Practice

Harry P. Erba, MD, PhD:So how would you handle this concern? You have a patient with CLL [chronic lymphocytic leukemia], 65 years old, and you can give them 6 months of chemotherapy, let’s say BR [bendamustine/rituximab]. Or you can give them continuous BTK [Bruton tyrosine kinase] inhibition as long as there’s no progression and there’s no toxicity. You have different competing toxicities there with chemotherapy—infection, risk of MDS [myelodysplastic syndrome]—but you have significant long-term toxicities that we’ve seen with the BTK inhibitors. Do you think there’s still a role, despite the PFS [progression-free survival] benefit, of starting with chemotherapy?

Anthony R. Mato, MD, MSCE:I think it’s very minimal at this point.

Harry P. Erba, MD, PhD:Minimal?

Anthony R. Mato, MD, MSCE:A minimal role.

Harry P. Erba, MD, PhD:Of chemotherapy?

Anthony R. Mato, MD, MSCE:Yes. I think we have shifted. Trials, particularly over the last year, have really helped to put the nail in the coffin for chemotherapy as a first therapy for patients. I think the one caveat to that is theIGHV-mutated, non-17p patients. It’s still a conversation that needs to be had. But we’re moving more and more away from single-agent targeted therapies to combinations of targeted therapies. And so, I think the role of chemotherapy has diminished. I personally haven’t given anyone BR [bendamustine/rituximab] or FCR [fludarabine/cyclophosphamide/rituximab] in a couple of years.

Harry P. Erba, MD, PhD:There’s also a practice difference, in terms of the patient coming to your office and giving that patient chemotherapy in your office as opposed to sending them home with a pill. Do you think that influences treatment decisions? That’s a tougher question.

Anthony R. Mato, MD, MSCE:I think it may, but I also think that probably the deficiency in many practices is that they’re not yet set up for oral targeted therapies. A lot of practices are hospitals, either community or academic, and have these great infrastructures for giving infusions. They have nurses to pay attention to those patients, to infuse the therapies, to asses for toxicities. We don’t really have a nursing pharmacy infrastructure—not we, but in general, the oncologic community—to manage these patients where you hand them a bottle, send them home. But they also have equal risk of having problems, infections, fevers. The need for laboratory monitoring for different things, like opportunistic infections, liver toxicity, for example. So I think that’s what needs to happen next, that as we make this shift, that practices in academic centers actually put the resources in place to manage these patients.

In CLL, we’re heading toward a time where the infusion bays are going to be largely empty of patients getting cytotoxic therapy. And as that time comes, we need to figure out how to manage these patients, outpatient, out of the office, mostly from home.

Harry P. Erba, MD, PhD:Those comments lead right into the next thing I wanted to discuss with you, which is exactly that. What do you tell your patients when you’re prescribing this? You know, “When are you going to call us with a problem?” What do you tell your nurses on the front line who are handling these calls from patients?

Anthony R. Mato, MD, MSCE:Fortunately, in our situation—it’s not just me, we have a whole program in place with nurse practitioners, research nurses, program nurses, pharmacists who are all attuned to the patients who are receiving therapies—we essentially see them all together in clinic. When patients are starting, they’re highly educated, in terms of the adverse events [AEs] that could happen. They’re used to fielding the calls from the patients. They know what to do. They know if a patient is receiving idelalisib and they call with a subtle cough, or a few episodes of diarrhea, this could be pneumonitis, this could be colitis, they bring them right in. They know for a patient who was on ibrutinib and are taking some steps and feel a bit weak, “Hey, maybe they have an occasional palpitation. This could be AF [atrial fibrillation]. We need to bring them in. We need to assess them.” So after they see the physician, most of the care outside of the doctor visit is by the team. And they are, by far, the most important people in helping patients to stay on these drugs.

Harry P. Erba, MD, PhD:And as we move more toward oral oncology drugs, I think there really has to be a change in how we are reimbursed for our efforts in taking care of these patients. The things that you’re describing are not things that we can usually bill for to sustain that practice of supporting nurses, and nurse practitioners, and pharmacists.

Anthony R. Mato, MD, MSCE:Correct.

Harry P. Erba, MD, PhD:Way beyond what we’re going to talk about today.

Anthony R. Mato, MD, MSCE:Yes, the revenue structures of hospitals, I don’t think I understand them well enough. But certainly, I agree with you. There needs to be resources committed to support these things because they’re not free.

Harry P. Erba, MD, PhD:So effectiveness not only depends on compliance related to discontinuations from AEs, but also on adherence of taking a medication. What do you do? Do you talk to your patients? Do you let the pharmacist or nurse talk to them about how to do this?

Anthony R. Mato, MD, MSCE:All of us do. We try to see them fairly frequently in the beginning to assess how it’s going. Are they taking their medications? We try to keep track if they refill them on time. You know, all of these things. But we don’t have a formalized algorithm for measurement of adherence in clinical practice. Very few places do. We’re not asking patients to keep pill diaries like we would on a clinical trial, or to bring back empty bottles. So, there’s some room to go. I think it’s important to have a good relationship with your patient, educating the patient as to why it’s important to stay on a drug from the perspective of managing the disease and also minimizing resistance. And then, seeing them frequently enough so that it’s not like an every-6-month touch base. You see them enough so that they can let you know there’s a problem so you can intervene. There is no 1 right answer.

Harry P. Erba, MD, PhD:So in CML [chronic myeloid leukemia], we’ve had data on adherence to oral TKI [tyrosine kinase inhibitor] therapy and responses. Are there actual data out there about that? It makes sense, but are there data?

Anthony R. Mato, MD, MSCE:Very minimal. There’s data from clinical trials that support that interruptions of 7 or more days may impact outcomes. But then, from clinical practice, we don’t see those same findings, probably because the trial patients were very different. They were sick to begin with. We don’t have a lot of information about how dose, or dose interruptions, or length of interruptions impacts clinical outcomes. It’s just barely studied.

Harry P. Erba, MD, PhD:We know when we start BTK inhibitors, they somehow change the location of these cells from spleen and lymph nodes into the blood. Is there a white count that you worry about or?

Anthony R. Mato, MD, MSCE:Not really. You can see the white count go up 5-fold when you start these drugs. Interestingly, only about 70% have a lymphocyte redistribution. There’s a good 20%, 30%, where the white count just goes down, and I’m not really sure anyone understands who those people are or why that is. In the beginning, I think people worried—400,000, 500,000—whether they should be debulked before they went on these drugs. I personally don’t know of any patient who had leukostasis because of a lymphocyte redistribution in CLL. People argue a little bit more in mantle cell lymphoma that there’s a higher risk, especially when you get to that, I think the magic number on the label for ibrutinib at one time was 400,000. I don’t know if it’s still there. But I think the risk is low.

Harry P. Erba, MD, PhD:So with that early lymphocytosis, that would not say to you, “Oh, you need to add in rituximab, or obinutuzumab?”

Anthony R. Mato, MD, MSCE:No.

Harry P. Erba, MD, PhD:OK.

Anthony R. Mato, MD, MSCE:Not as a standard approach. Maybe there are one-off examples where I’ve added in a CD20 because there was active, rip-roaring hemolytic anemia that I thought needed to be addressed sooner than the BTK might address it, if it did. But those are examples of 1 or 2 cases. They’re not the norm.

Transcript edited for clarity.