Case 3: Response to Frontline Therapy and Toxicity Management



Matthew S. Davids, MD, MMSc:So, as you think about this case, putting together that high-risk clinical feature, some of the high-risk molecular features, and, as we talked about, we have a number of different chemotherapy-based options (we have novel agents), what would you think about for treatment of this patient?

William Wierda, MD, PhD:The feature that drives my choice of treatment for this patient the most is the presence of the mutatedTP53. The use of chemoimmunotherapy is really contraindicated, in my mind. We get toxicity with very little clinical benefit from chemoimmunotherapy for these patients. We have a very active drug that’s approved in the frontline setting (ibrutinib), which would be my choice for treatment for this particular patient. There is an expectation of good outcome and response to treatment with ibrutinib monotherapy.

Matthew S. Davids, MD, MMSc:Great. This patient was, in fact, started on ibrutinib at 420 mg daily—the standard dose. Initially, the patient did develop some grade 3 neutropenia after about 4 weeks on therapy, but this was managed with some growth factor support. It later resolved. They were able to continue dosing at full dose. The patient’s symptoms improved quite dramatically over the course of the first 6 months of therapy. The splenomegaly and hepatomegaly resolved. The pleural effusion did require some additional thoracenteses over the first few months, which is pretty common. Eventually, that improved as well. The lymph node size was reduced by about 80%.

About 6 months after starting ibrutinib, the laboratory results looked much better. There was still a lymphocytosis, as is commonly seen at 6 months. The patient’s total white count was around 32. By that point, his hemoglobin had already improved to 11.4. Platelets were up to 143, the LDH remained normal, and the beta2microglobulin had come down.

Now, we’ve had this 75-year-old patient on ibrutinib for several months, and it’s likely that we’ve run into some toxicities. We heard a little bit about some neutropenia, but there are other ibrutinib-related toxicities. Dr. Jain, may you take us through some of the common toxicities that we see? How might we think about them?

Nitin Jain, MD:Sure. With ibrutinib, I tell my patients that common toxicities include loose stools and diarrhea, skin rash, and arthralgias. All of these are seen in 20% to 40% of patients. So, that’s important to point out to patients. Another toxicity of importance is hypertension. For patients who are already hypertensive, who are on 1 or 2 medications, once they start ibrutinib, it’s not uncommon to have to either increase the doses of the medications or add an agent.

The other less common but more significant toxicity would be atrial fibrillation, which is seen in up to 10% of patients. Some studies quote a higher number. But again, that’s an important toxicity to recognize as well as manage, also from the standpoint of anticoagulation. Typically, for a patient with atrial fibrillation, in our practice, we hold ibrutinib if it is a first occurrence. We consult the cardiologist to see whether they want to rate-control or rhythm-control the patient. We receive the input of the cardiology team, in terms of anticoagulation for the patient. With respect to anticoagulation, Coumadin is typically contraindicated with the use of ibrutinib. But there are other new oral anticoagulants that can be used. For the first episode, we typically restart the patient at the same dose. If it recurs again, then the recommendation would be to go down by 1 dose level.

The other important aspect with ibrutinib is the concern for bleeding complications. Ibrutinib has an antiplatelet effect. There have been cases of serious bleeding, including CNS bleeding. So, that’s also something to watch for when your patient is on ibrutinib. There are recommendations, for patients who are undergoing surgical procedures, to hold ibrutinib pre- and post-procedure. Again, this is something to recommend to the patient.

Matthew S. Davids, MD, MMSc:Dr. Wierda, we’ve seen somewhat conflicting data sets coming out in terms of what the clinical trials show for ibrutinib toxicities. Some of these studies of “real-world” data reveal much higher rates of toxicities. What is your perspective on this?

William Wierda, MD, PhD:Well, the truth always lies somewhere in the middle. There’s a lot of conformity, and there are rules that we need to follow for clinical trials. Patients are very motivated. And so, the profile for toxicity, although it’s collected very diligently, may be somewhat different from what is seen in the community. There are inclusion criteria that we have on our clinical trials. The fitness of the patients may not be exactly what it is in the community. We know that this disease is most common in people over age 70. Those are usually not the patients who are participating in clinical trials. If they’re over age 70 and are participating in a clinical trial, they’re usually very motivated. If they are very mobile, they can come to an academic center. So, there are probably differences in terms of the patients who are enrolled in clinical trials versus the patients who are treated out in the community. Again, I think the truth is somewhere in the middle. Concerns for toxicities, etc, certainly need to be considered.

Transcript edited for clarity.

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