Management of Toxicities in Frontline Ibrutinib Therapy

Matthew S. Davids, MD, MMSc:Another important dataset that has emerged over the last year is the longer-term follow-up of the RESONATE-2 study. As a reminder, this was the randomized phase III trial of older, frailer CLL [chronic lymphocytic leukemia] patients needing frontline therapy where patients received either ibrutinib or chlorambucil. This study was previously reported to be positive and led to the frontline approval of ibrutinib, and more recently we saw about 4 years of follow-up on these initial patients, about 135 or so who were treated with ibrutinib.

Of course, the ibrutinib arms continued to look better than chlorambucil, as we expected. But I think what was more important was looking at some of the longer-term follow-up numbers. These suggested close to a 90% rate of progression-free survival for the ibrutinib patients at 2 years, with ongoing durable responses in many of these patients now at 4 years or longer. So it does suggest a durability to the response.

We did also see in this study about 12% of patients needed to discontinue ibrutinib due to other reasons, and these included toxicities or other adverse events. So we need to be mindful of some of the toxicities of ibrutinib, and these include atrial fibrillation, bleeding risks, and other things such as the myalgias, arthralgias, infections, and rash. So these are considerations as we manage patients with ibrutinib. As these toxicities arise it doesn’t necessarily mean that we need to completely discontinue the drug. But sometimes we need to pause and discontinue temporarily, allow these [adverse] effects to recover, and then think about resuming, sometimes with a dose reduction. But with most patients we can get them through these ibrutinib toxicities over time and they tend to do well in the long term.

In the comparative studies of ibrutinib versus, for example, bendamustine and rituximab, the ibrutinib arms certainly do look favorable from a toxicity profile. We tend to see lower rates of cytopenias from ibrutinib compared with chemoimmunotherapy. We see lower rates of febrile neutropenia and the more serious bacterial infections. So all that is favorable. I think also the convenience of an oral therapy is an important thing for patients compared with infusional chemoimmunotherapy. As we look at the longer-term patients on ibrutinib, and generally they tend to do quite well, we do not tend to see cumulative toxicities, but we do have ongoing risks of bleeding and bruising and things like atrial fibrillation, as well as hypertension that can develop later in the course of ibrutinib. And so these are things we all need to be mindful of in patients who are on longer-term ibrutinib therapy.

In terms of the different toxicities of ibrutinib, atrial fibrillation tends to be one that we can manage. Usually it does require interruption of the ibrutinib, at least temporarily. To me the bigger challenge of the atrial fibrillation is that for our older patients, they typically do meet criteria for starting anticoagulation to prevent stroke. And then when we go to resume the ibrutinib we have a patient who is on anticoagulation and also on ibrutinib, which as we know can increase the risk of bleeding and bruising.

So that is a challenge with the drug, but I think that overall most patients tolerate it well. The atrial fibrillation is generally manageable. But I think as more alternatives come along that it will be interesting to see how things go in terms of whether patients will be switched to other drugs that may not have as much risk there.

I’ve used ibrutinib now for several years, and I have a number of patients who are on long-term therapy, and I would say in general those patients have been doing very well. I tend to find in my population that when we see toxicities it tends to be early on, often within the first weeks or months of starting the ibrutinib. I have not seen as much in the way of later toxicities. So my patients now who have been on ibrutinib 4 or 5 years or even longer are doing very well in general.

So quality of life on ibrutinib for most patients is very good. If we take the patient in our case example here, this is a patient who’s feeling pretty poorly right now. He has fatigue, he’s had unintentional weight loss, lymph nodes that are uncomfortable. One of the first things I often find patients remark on is that their lymph node disease can begin to shrink down really right away after starting ibrutinib. Within a few days they notice that that improves.

The fatigue can take a little longer to improve and eventually most patients will put weight back on. But quality-of-life-wise, patients tend to do very well on ibrutinib if they’re tolerating the drug well. Chlorambucil is also a pretty well tolerated drug, but it’s not something that we use very widely.

As we compare ibrutinib to bendamustine and rituximab, I think the quality of life is different. With bendamustine and rituximab, they are coming in a couple of days out of the month for infusions. There are other toxicities and fatigue and nausea and things like this. With ibrutinib I find that it tends to be well tolerated for most patients, but there are some other more nagging [adverse] effects that we see. We can see diarrhea on ibrutinib in 40% or so of patients.

We can also see myalgias or arthralgias, which can sometimes be problematic. Again, not a reason necessarily to completely discontinue ibrutinib. Sometimes we need to hold the drug and give supportive measures with NSAIDS [nonsteroidal anti-inflammatory drugs] or other adjuvant types of therapies for pain. Usually when we resume ibrutinib we can start with the dose reduction first to see if that helps. And some patients may just need a lower dose of ibrutinib to get around this arthralgia issue. But it’s not necessarily a reason to move away from the drug.

Transcript edited for clarity.

Case:A 74-Year-Old Male WithIgVH-Unmutated CLL

• A 74-year-old male presented to PCP with complaints of extreme fatigue, weakness, and weight loss of ~15lbs over the last 3 months.
• PMH: Mild hypertension managed by statin
• PE: BP 135/85, enlarged lymph nodes (~6cm), palpable spleen approx. 7cm below costal margin
• Laboratory findings:
  • WBC; 100 X 10⁹/L
  • Lymphocytes; 82 X 10⁹/L
  • Hb; 15.1 g/dL
  • Platelets; 125 X 10⁹/L
  • ANC; 1,800/mm³
  • LDH 250 u/L
• β2M, 4.3 mg/L
• FISH; normal
• Molecular analysis;IgVH-,TP53wild-type
• ECOG PS 1
• Rai Stage II