Evaluating Ibrutinib's Safety and Efficacy in WM


Jorge J. Castillo, MD:At this time, we have 3 ibrutinib studies that have been published. We do have a database of 300 patients off study that we are treating in the clinic. My impressions in terms of the efficacy is that it is an efficacious regimen. When we follow patients and evaluate them based on the current guidelines that we have for response, over 90% of these patients will respond with a decrease in the serum IgM [immunoglobulin M] levels. Not only that, but we have also seen patients’ anemia improving, with some patients’ thrombocytopenia improving, lymphadenopathy improving, splenomegaly improving, and hepatomegaly improving. We have actually seen benefits in these patients. The quality of life of these patients improves greatly as well. The efficacy is there, and obviously, the depth of our efficacy—how long that efficacy lasts—is something to be seen as time goes by.

In our parent study, in which we have been following patients for over 5 years, not even half of the patients have stopped taking ibrutinib. They continue taking ibrutinib 5 or 6 years out. We feel the patients in the frontline study will have a very similar outcome in that specific situation. Now, the safety profile is different. It’s different than the chemotherapy agents that we have used. The fact that you have to take 1 pill every day indefinitely makes the adverse effect profile very different to what we have been used to. I would divide the adverse events associated with ibrutinib into 2 groups. I would say there’s early stage adverse effects and then late adverse effects.

The early adverse effects we have seen are typically nausea, diarrhea, rash, and joint pains. Most of these symptoms will resolve within the first 2 or 3 months of therapy and will not be longstanding. Of the late adverse effects, there are 2 that we need to talk about that are probably important. One of them is the risk of bleeding. Ibrutinib does block the stickiness of platelets. It affects the addition and aggregation, so patients can bleed if they get exposed to a trauma or surgery while on ibrutinib. But this is easily manageable as we can stop ibrutinib for a few days prior to, the day of, and a few days after any procedure. Depending on how invasive the procedure is, we do have specific durations of holds to minimize the risk of bleeding. That is not too big of a problem.

The other problem is a novel adverse event in terms of arrhythmias. Atrial fibrillation is probably the most common arrhythmia in the country without Waldenström macroglobulinemia, on or off of ibrutinib. But we believe that patients on ibrutinib have a little higher risk of developing this arrhythmia down the road. We see it a few years into therapies. It’s not a very early problem. Now, there are some data showing that older patients, or patients with prior history of arrhythmias or prior history of heart problems, have a higher risk of developing this issue. Patients who are younger and don’t have any other conditions are at lower risk of having this problem, but it’s something that we need to be aware of. We need to learn how to manage it appropriately.

From what I’ve seen, ibrutinib tends to be a good agent. Our patients, the patients who have specifically been previously exposed to chemotherapy or monoclonal antibodies and have had reactions to them, or who have previously been exposed to transplants and things of that nature, really feel ibrutinib is the next best thing that ever happened to them. If those patients are really well selected, we will know which ones are going to derive the best benefit out of this. I think that’s what the trick is, trying to really understand who’s going to be the best patient to derive benefit from this.

In our practice, about 60% of patients haveMYD88mutations withoutCXCR4mutations. Those patients are feasible candidates for ibrutinib. I think those are the patients who will benefit the most from this type of therapy. About 30% of patients will have aCXCR4mutation. I don’t want to say that those patients do not benefit from ibrutinib—I think they do—but there are other options that are equally effective, such as bendamustine or bortezomib in combination with rituximab. We need to make some decisions on what makes the patients more favorable in terms of how to treat them. If patients have noMYD88mutation, those are the patients who would not benefit from it or will benefit the least from ibrutinib. In those patients, I try to use rituximab combinations and whatever is more standard to treat them with.

Specifically in this case, treatment with ibrutinib should be indefinite. We don’t have any data at this time showing ibrutinib therapy can be stopped. It doesn’t matter how deep the response gets. Every time we have tried to stop ibrutinib therapy, it takes a few days for the IgM to start climbing. In about 80% of patients, within 3 months, they are back to where they were at the beginning of therapy. There is no reason to stop ibrutinib therapy at this time, and our recommendation is to continue indefinitely.

Transcript edited for clarity.

Case: A 65-Year-Old Female With Newly Diagnosed Waldenström Macroglobulinemia

September 2016

  • A 65-year old female presented to her PCP with slowly progressing anemia for the last couple of years
  • Several months prior to that, she began experiencing drenching night sweats, distended abdomen, and 15 lb weight loss
  • SH: Married, exercises regularly, social drinker, non-smoker, no illicit drug use
  • FH: Maternal aunt — breast cancer age 51
  • Laboratory results:
    • Hemoglobin; 7 g/dL (11-13 g/dL), platelets; 55,000/mm3(155,000-410,000/mm3), and leukocyte count 1,700/mm3(3,800-9,200/mm3).
    • M-protein; 2991.3 mg/dL; IgM 4710 mg/dL (45—281 mg/dL)
    • Serum viscosity; 3.7 centipoise (cP) (1.6—1.9 cP)
    • Beta-2; 3 mg/L (0-2.7 mg/L)
    • IPSSWM: 2 Intermediate
  • Bone marrow aspiration and biopsy; 40—50% B cells
  • Flow cytometry; Lambda-restricted B cells that expressed CD19 and CD20
  • B cells were negative for CD5, CD10, CD43, bcl-1, and bcl-6
  • Allele-specific PCR; MYD88L265Pmutation
  • Diagnosis; Waldenström’s macroglobulinemia (WM)


  • Patient was started on ibrutinib (420 mg) daily with monthly follow-up visits
  • After three months, her IgM was 1500 mg/dL and her serum viscosity was 1.5 cP
  • Her CBC showed improvements: WBC, 5000/mm3, Hgb 15.5g/dL; platelets 180,000/mm3
  • The patient was last seen on follow-up last month and she continues on ibrutinib 2 years after her initial presentation
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