BTK Inhibitor Toxicities in Mantle Cell Lymphoma

Jonathon Cohen, MD, MS: Ibrutinib and the other BTK [Bruton tyrosine kinase] inhibitors are very well tolerated in most cases. If you look at the data, especially in CLL [chronic lymphocytic leukemia] as well as mantle cell lymphoma and other disease histologies, you can see that a large number of patients are able to stay on treatment for a very long time. Having said that, there are a number of key toxicities that everyone needs to be aware of. Some may be mild but annoying over time, and others can be life-threatening.

Ibrutinib, in particular, has been associated with life-threatening bleeding complications. This does not mean that a patient cannot be on anticoagulation at the same time, but certainly, those are patients for whom you need to really think carefully about whether it’s appropriate for them to be on ibrutinib or whether they could potentially discontinue the anticoagulation. We do know that patients receiving ibrutinib would hold ibrutinib before any surgical procedures. Certainly, if they were to be in a car accident or have any other trauma they would be at an increased risk for bleeding.

In addition, we know that ibrutinib can be associated with an increased risk of atrial fibrillation. Given that it’s frequently administered to patients in their 60s or 70s, which is a time when atrial fibrillation and other cardiac complications tend to emerge anyway, close observation is required.

Some less severe but also important toxicities can include arthralgia, hypertension, as well as diarrhea and rash. These are things that may not necessarily require a patient to discontinue the medicine, but you can imagine having even mild diarrhea over a long period of time can be problematic. It’s at least important to mention it to patients so they can feel comfortable bringing it up if it were to happen to them.

Finally, although this is not chemotherapy per se, there has certainly been some increased risk of infections for patients on ibrutinib. I tend to incorporate antimicrobial prophylaxis with antivirals as well as with Bactrim [sulfamethoxazole, trimethoprim] when feasible for patients who are receiving ibrutinib. It’s important that patients recognize that although they’re not receiving traditional chemotherapy, they are at increased risk for infectious complications, and this does need to be monitored.

Finally, I would also point out that although not a physical toxicity, there can be some significant costs associated with ibrutinib. Patients are sometimes not overly enthusiastic about sharing this concern. At our own center, and I’m sure at a lot of your centers, there are folks who are available to help with patient-assistance programs. The companies themselves also have a number of opportunities to help make it more feasible for patients to obtain medication over a long period of time. But it’s important to have this discussion with patients, because the financial toxicity of long-term therapy can certainly be disabling for some patients.

It’s important for patients who are on ibrutinib to have routine follow-up appointments with their oncology team. Even though a patient may be taking a medication at home and may be doing well and responding well, there can still be toxicities that emerge. Fortunately, most adverse effects with ibrutinib will actually get better with time. But certainly, even some chronic low-grade toxicities like diarrhea need to be discussed with the team. Often, these are toxicities that can be easily managed, and the patient can remain on therapy. Where we sometimes run into issues is when a patient doesn’t necessarily disclose some of these toxicities. Eventually, it gets to the point where they feel that they can’t take the medication anymore. It may have been something that could have been intervened upon earlier in the course and the patient may have done just fine.

Transcript edited for clarity.

Case: A 68-Year-Old Male with Mantle Cell Lymphoma

Initial presentation

• A 68-year-old man presented with generalized lymphadenopathy, fatigue and an unintentional 8-lb weight loss
• PMH: HTN, medically controlled
• PE: abdominal distention, splenomegaly
  
  

Clinical workup

• LDH 345 U/I, ANC 3500/mm3, beta-2-microglobulin 4.4 µg/L, leukocytes, 5.98 X 109/L, hemoglobin 9.6 gm/dL
• FISH: t (11;14)
• Immunocytochemistry: cyclin D1+, CD5+, CD20++
• BMB positive for lymphoid cells with cyclin D1
• PET/CT scan showed widespread lymphadenopathy in numerous nodal regions including left mesenteric (3.4 cm), bilateral axillary (3.9 cm, 5.3 cm), and cervical (5.1 cm)
• Ann Arbor stage IV; MIPI score 6.3; ECOG PS 1
  
  

Treatment

• Patient was started on bendamustine + rituximab
  • Achieved PR
  • Continued on maintenance rituximab q8W
• At 9 months the patient had clinical disease relapse
  • He was started on ibrutinib 560 mg PO qDay
  • Imaging at 12-week follow-up showed no evidence of disease