Potential Ibrutinib Toxicities

Nicole Lamanna, MD: Ibrutinib is frontline and has been approved for any patient previously untreated as well as relapsed and 17p deleted patients. But let’s talk about some of the adverse effects of ibrutinib. There are also many second-generation BTK [Bruton’s tyrosine kinase] inhibitors that are also being evaluated right now. So stay tuned for their toxicity data, and some of the head-to-head with ibrutinib will eventually be emerging.

We know that ibrutinib, when I talk to patients about initiating therapy, there is some potential short-term adverse effects of the drug as well as some potential continuous adverse effects. The most that patients and physicians are concerned about, of course, have to deal with cardiac arrhythmias, most commonly being atrial fibrillation, although they could have others, and folks who might be on anticoagulant drugs, antiplatelet agents for other reasons, whether they be cardiac reasons or other reasons.

There is a concern, because we know that ibrutinib does have a slightly increased risk of bleeding. And so then if you add ibrutinib to somebody who is already on an anticoagulant agent, there’s concern about enhanced bleeding, or bruising, or obviously more seriously a fatal bleed. We have very good follow-up data that suggest it’s not that you cannot not use ibrutinib with anticoagulants. I think you can. Do I think you have to be cautious? Absolutely. I think we have pretty good follow-up data even from the phase I study of ibrutinib, both in the frontline and relapsed settings, showing that major risk of hemorrhage is low, on the average, depending upon the study, somewhere between 3% and 5%. The atrial fibrillation, however, or cardiac arrhythmias probably have increased because we have longer follow up than the initial studies. The initial studies reported somewhere about 5% to 7%, with long-term follow-up data anywhere probably now from 10% to 15%. That is a real risk that you need to discuss with patients, who, when you start discussing some of the adverse effects of these medications, who will absolutely say, “I’m too afraid of this and I do not want that and give me something else.” And I can’t say that’s unreasonable because there are many more choices now than there were ever before.

But are they manageable? Yes. I mean, we used to manage a lot of adverse effects just with chemoimmunotherapy, and so as with newer therapies, we learned to manage those adverse effects with the BTK inhibitors. We’re hoping that some of the newer BTK inhibitors, that their adverse effect profiles will be better, so they have reduced cardiac arrhythmias and bleeding risks. That remains to be seen when the data will eventually get presented, hopefully. And, if so, that may be a game-changer for ibrutinib if there are other drugs that have fewer adverse effects and are equally efficacious.

The other adverse effect that people get concerned about with ibrutinib is hypertension. And, of course, being that our patient population is older to begin with—remember the median age of CLL [chronic lymphocytic leukemia] is 70, 72—many of these patients already have comorbidities, including hypertension, diabetes, and heart disease. Many of them are on the medications to help with these other medical problems. So you do have to co-manage, potentially, adverse effects while the patient is on ibrutinib, with their internist or their cardiologist. If they’re on antihypertensive medicines, they can be tweaked if their blood pressure gets higher. I think there is a concern for folks who don’t have cardiac issues and then develop atrial fibrillation. If they were never on blood thinners or blood pressure medicines and then all of a sudden you tell them they’re going to stay on them, for some individuals, if they develop atrial fibrillation, they choose not to because they really don’t want to have to be on all these extra medications and all these cardiac medications.

So there is no doubt, with some of the toxicities that we see, you do have to have an open view with your patient whether they’re comfortable co-managing them because they’re all manageable. But whether the patients want to pursue and stay on ibrutinib or change to another agent always does come up and it’s a frank discussion. But I don’t think that if somebody is on an anticoagulant per se, ibrutinib is completely contraindicated. I think that we’ve seen plenty of folks who are on ibrutinib and anticoagulants who are doing well. But you have to make them aware that they are at an increased risk of bleeding and obviously to stop the agents before any surgical procedures.

There are some nuances that you have to take when somebody is on ibrutinib and anticoagulants or even on ibrutinib alone. And you educate your patients, and the more familiar that oncologists become with using these novel agents, the better that they will be at managing any of the adverse effects to any of the novel agents that are coming across our path. It’s just taking a little bit time and a little bit of education and experience. And now there are going to be many options, so certainly then I think there will be more room to pick and choose, depending upon your patients’ comorbidities.

Transcript edited for clarity.

A 58-Year-Old Man With Relapsed CLL

• A 58-year—old man presented with symptoms of fatigue and left upper quadrant fullness
• PMH: cervical lymphadenopathy, ~2.5 cm; spleen, palpable ~6 cm below left costal margin
• PE: vital signs WNL, right cervical lymphadenopathy, spleen palpable 5 cm below costal margin, otherwise well-appearing
• Laboratory findings:
  • WBC, 160,000; 68% lymphocytes (ALC, 112,000 cells/mL)
  • Hb; 9.4 g/dL
  • Platelets; 130 X 10⁹/L
  • ANC; 174/mm³
• Flow cytometry; CD5+, CD19+, CD23+
• Cytogenetics, IgVH unmutated; del 17p
• β2M, 4.0 mg/L
• BM biopsy; diffuse infiltration by CLL
• Diagnosis; chronic lymphocytic leukemia
• The patient was treated with fludarabine, cyclophosphamide, and rituximab and achieved a complete remission

Three years later, on routine follow up

• Laboratory findings:
  • WBC; 93,000; 97% lymphocytes
  • Hb; 10.4 g/dL
  • Platelets; 123 X 10⁹/L
  • ANC; 1,600/mm³(WNL)
  • LDH; 242 U/L
  • Beta-2-microglobulin; 9.1 µg/L