Jonathon B. Cohen, MD, MS

 We are lucky, at the current time, to have 3 approved BTK [Bruton tyrosine kinase] inhibitors for patients with relapsed/refractory mantle cell lymphoma. Ibrutinib was the first to be approved, but we now also have acalabrutinib as well as zanubrutinib. It’s important to recognize that at least as of right now, these have not been compared head to head. So it’s difficult to really draw firm comparisons between the 3 with regard to their efficacy and tolerability. Having said that, we have seen some themes emerging. It does appear that some of the newer BTK inhibitors may have some decreased toxicity, although it’s also important to recognize that acalabrutinib, for example, has been associated with an increased risk of headaches. This has not necessarily been seen with ibrutinib.

I think 1 of the key facts to keep in mind is that the other BTK inhibitors were developed after some of the initial trials with ibrutinib showed promise. In addition, many of the toxicities that we have come to identify with ibrutinib were already described at that point. Maybe patients who were at risk for some of these toxicities might not have been put on acalabrutinib or zanubrutinib studies. Really, to tell the difference among these groups, we’ll need head-to-head studies. Many are being considered and are under way, but it will be some time before we can really make any definitive comparisons.

When I’m evaluating a patient in clinic, I often take into account a number of factors, not the least of which is the ease in obtaining the medication and whether one might be associated with a lower co-pay. In my own practice, I’ve seen a difference in co-pay of up to $100 a month, and it’s not always the same drug that is cheaper. So it’s important to work with your pharmacy staff to see if you can get 1 of these medications at a lower rate based on the patient’s prescription drug coverage.

Also, although there hasn’t been direct head-to-head comparison, it does seem as if there may be fewer bleeding complications and cardiac complications with some of the newer BTK inhibitors. For a patient with a history of atrial fibrillation, for whom I think a BTK inhibitor is critical, I might consider 1 of the newer versions of the medication.

At the end of the day, I really can’t definitively state that there are significant differences among these therapies. It often comes down to more practical matters like cost, for example; some require twice-daily administration while others are daily administration.

Despite the fact that we now have a number of effective therapy options and that patients with relapsed/refractory mantle cell lymphoma are living longer than in the past, the overwhelming majority will unfortunately still die from their disease. Ibrutinib, as good as it is, is unfortunately still associated with an ongoing risk for relapse the further out you go. And we know that there can be ongoing toxicity. For a patient with relapsed/refractory mantle cell lymphoma, it’s important to really balance this toxicity with long-term goals of care and long-term efficacy.

Fortunately, we do have some other more intensive options. Allogeneic transplantation can, in some instances, be curative for a highly selective group of patients. It’s important, especially for our younger patients or those who have relapsed early or multiple times, to at least have this discussion about the potential role of allogeneic stem cell transplantation.

In addition, many of you are likely familiar with the fact that CAR [chimeric antigen receptor] T-cell therapy, currently approved for large B-cell lymphoma, has been evaluated in mantle cell lymphoma and looks very promising. I don’t know exactly where CAR T-cell is ultimately going to fit into the management algorithm of patients with mantle cell lymphoma, but it will certainly require discussion and will be an excellent therapy option for patients in the future.

Finally, it’s important to recognize that many of these therapies work very well as monotherapy but could work even better in the setting of a combination. The hope would be that they remain quite well tolerated. One good example is lenalidomide, which has been approved for mantle cell lymphoma in patients who have progressed after bortezomib. We know that lenalidomide monotherapy is not nearly as effective as lenalidomide in combination with rituximab. For example, I often think about using rituximab with lenalidomide in patients with relapsed mantle cell lymphoma. My expectation is that there will be ongoing studies of combinations, and we may find that particular BTK-containing combinations are more effective than BTK inhibitors as monotherapy.

I think the future is very bright. A lot of discussion and a lot of testing will be needed to figure out the right sequence of therapies, right combinations, and where some cellular therapies fit in. These are all the subject of intense debate and clinical trials in the current time.

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

A 68-year-old man presented with generalized lymphadenopathy, fatigue and an unintentional 8-lb weight loss

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

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



Patient was started on bendamustine + rituximab

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

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Next Steps in Relapsed/Refractory Mantle Cell Lymphoma

 Traditionally, we have thought that ibrutinib, although it’s incredibly effective in mantle cell lymphoma, has not been associated with true long-term progression-free survival. It’s been thought that it’s unlikely that we’re curing patients who have relapsed mantle cell lymphoma. For most patients, unfortunately this is the case. They tend to respond well, but will most likely ultimately progress and require additional therapy. There have been, however, recent studies, including 1 presented at ASH [American Society of Hematology Annual Meeting] this past year, that have pooled several clinical trials and looked at the outcomes for patients who received ibrutinib for relapsed/refractory mantle cell lymphoma on those studies. There have been a few key findings. The first is that it does appear that taking ibrutinib earlier on in the course of therapy—typically after your first line of therapy as opposed to later on—has been associated with an improvement in progression-free survival compared with taking ibrutinib later in the course—as a third or fourth line of therapy or beyond.

It’s important to interpret these data with a bit of a grain of salt. Certainly, any treatment is likely to be more effective if you take it earlier on in the disease course as opposed to if you take it later in a disease course. But the findings for ibrutinib have been particularly striking. The other thing we’ve started to see is that there is a small percentage of patients who have stayed on ibrutinib for several years who remain in remission. If you actually look at the Kaplan-Meier curve, you can see that by the time you get that far out, only a handful of patients are still being evaluated. Some patients have been censored, and many patients have unfortunately progressed or died either of their disease or from other causes. But it does suggest that there’s probably at least a small number of patients who will enjoy a prolonged remission on ibrutinib. Certainly, administering it earlier in the course of therapy does appear to increase the likelihood of achieving this long-term remission.

In the case that we reviewed today, the patient had received bendamustine-rituximab, which is a very commonly utilized frontline regimen. However, the fact that the patient then progressed within 9 months of treatment would certainly suggest to me that a chemotherapy-based approach is unlikely to be the most effective option in this case. In addition, this particular patient did not receive a stem cell transplant. Whether this was because maybe they had some other findings, or maybe they weren’t interested in such an aggressive course, it would suggest that therapy that we offer in the second-line setting and beyond is unlikely going to be highly aggressive or highly intensive.

Ibrutinib really makes a lot of sense in this case. This is a patient who doesn’t have any comorbidities that would prohibit them from receiving ibrutinib and can be expected to respond well. The fact that he has responded so quickly and with a complete remission makes me hopeful that he will be 1 of the long-term responders. Certainly, he’ll need continued observation, and we’ll want to be prepared to move forward with an alternative therapy if and when he progresses or develops some toxicity. But in the current scenario, it makes a lot of sense to use a therapy like ibrutinib, given the inferior response that he had previously to chemotherapy.

BTK Inhibitors in MCL: Long-Term Safety & Efficacy Data

 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.

BTK Inhibitor Toxicities in Mantle Cell Lymphoma

 We’re very lucky, at the present time, to have a number of different therapy options available for relapsed mantle cell lymphoma. Ibrutinib and the other BTK [Bruton tyrosine kinase] inhibitors are administered orally at home. Some are given once daily, and others are given twice daily. Then we also have other therapies that are administered intravenously, like bendamustine-rituximab, which is sometimes used in the relapsed setting, especially in a patient who hasn’t received that regimen previously. That’s administered in the infusion center by IV [intravenous].

There are advantages to both. Many patients think the idea of doing an oral therapy is a huge improvement over having to come into an infusion center to receive IV therapy. I tend to agree that this is a major benefit with this type of therapy. What’s important to keep in mind is that oral therapy is not necessarily for everybody. There can be financial concerns with regard to having to obtain that medication through a prescription drug plan, and there can be challenges with adherence. Anybody who takes a daily medication knows that it’s very difficult to take that medication every single day. I myself take an allergy medication, and I can tell you that probably once every week or 2 I forget to take it. When you’re talking about a medication like ibrutinib, it’s important that patients remain on therapy and take it every day. It requires a lot of counseling and a lot of reinforcement to patients that they take their medication every single day without fail.

In some patients, this is just a really challenging thing to do. Maybe they’re taking care of ill family members, or maybe they live in a situation where there’s a lot going on and they may just not have that opportunity to take a second medication every day. Again, it requires a real consideration of the patient, their home situation, and whether they’re going to be able to manage taking a daily oral medication. In some cases, coming to the infusion center once a month or every so often to get an IV infusion is a little easier for patients. They know they come for their appointment, get their treatment, and don’t have to worry about it when they go home.

Administration of BTK Inhibitors for Mantle Cell Lymphoma

 If you check the NCCN [National Comprehensive Cancer Network] Guidelines, you’ll see that there are a large number of different options available for patients with relapsed mantle cell lymphoma. In the past, patients would be treated with chemotherapy, which may have had moderate effectiveness. Unfortunately, those were often patients who passed away from their disease relatively quickly after the diagnosis of relapsed mantle cell lymphoma. Over the last several years, however, there have been a number of new therapies developed and a number of FDA-approved treatment options for patients. I often will try to use a BTK [Bruton tyrosine kinase] inhibitor in patients with relapsed mantle cell lymphoma at the first time of relapse. There are a number of reasons for whom this may or may not be feasible, but we do know that ibrutinib and other BTK inhibitors are highly effective in this setting. There are, however, a number of other options available, including bortezomib; and lenalidomide is also approved, especially in patients who have relapsed after bortezomib.

Again, there are a number of different therapy options. It really depends on the patient in front of you and their comorbidities and goals. One example may be that a patient may not be interested in continuous therapy. In cases like that, even re-treating a patient with a chemotherapy like bendamustine-rituximab may also be very effective. It really does require an in-depth conversation with a patient, consideration of comorbidities, as well as an evaluation of available treatment options.

The patient in our case received ibrutinib as their initial therapy at the time of relapse. In most cases, this would be my recommendation—to use ibrutinib or 1 of our other FDA-approved BTK inhibitors. We know from a number of different studies that the use of ibrutinib earlier on in the course of treatment tends to be associated with an improved progression-free survival compared with its use later on in the course of treatment. In addition, ibrutinib is generally well tolerated. Although there are some known toxicities that we counsel patients about, most people can be expected to tolerate therapy quite well and remain on treatment for quite some time. Compared with the other available options in the relapsed setting, it tends to compare very favorably.

I think ibrutinib certainly makes sense in this case. Although this patient responded beautifully and had a complete response, that isn’t always the case in patients who receive ibrutinib. In many cases there will be an excellent response, but there still may be some residual adenopathy. This is why we most frequently recommend that patients remain on ibrutinib indefinitely, or at least until they progress or have intolerable toxicity. In most cases, patients are not going to achieve a complete remission. In this case the patient did, and that’s wonderful, and I certainly would recommend that the patient continue on treatment. Hopefully this is 1 of the patients who is going to have a prolonged response to ibrutinib.

Relapsed Mantle Cell Lymphoma Treatment Landscape

 When trying to make a determination about the most appropriate therapy for a newly diagnosed patient, a number of different factors come to mind. Sometimes a patient may be entirely asymptomatic. Regardless of their age or underlying comorbidities, they may be perfectly suitable to be observed without any active therapy. I have patients in my own practice who were diagnosed 4 or 5 years ago and have not had any clinical evidence of progression of disease. We continue to monitor them, and I check on them a couple times a year. This is probably between 6% and 10% of all cases, so it doesn’t happen all the time but is certainly important to keep in mind.

In most other patients, however, you will need to make a decision about therapy fairly early on in the disease course. There are a number of different factors that I at least take into account when making a decision about a patient. In addition to the disease-related characteristics, it’s important to remember the patient in front of you. A patient with multiple comorbidities who is older or frail is not going to be a candidate for real aggressive therapy. On the other hand, the patient who is young and healthy should be considered for very aggressive therapy. Those may be the patients who can enjoy the longest duration of remission.

So there are a number of different factors that come into play, and therapy may range from purely palliative radiation treatment, to a course of single-agent rituximab or other therapies, all the way up to very aggressive combination chemotherapy followed by an autologous stem cell transplant. I think all things being equal, in a patient who does not have a 

 mutation, who otherwise is eligible for any therapy, I would still favor a cytarabine-based induction regimen followed by stem cell transplantation. However, there are studies underway that are exploring the need for autologous stem cell transplantation, especially if a patient has an excellent response to induction therapy.

When we initiate chemotherapy in patients with mantle cell lymphoma, the goal is to have those patients achieve a complete remission. What we mean by that is have the patient’s PET [positron emission tomography] scan reveal negative disease at the conclusion of therapy. Even though we know that patients are ultimately likely to relapse with this disease, those who achieve a complete remission are likely to stay in remission the longest. So that’s our goal when we start therapy. Although this patient had a good response, the fact that the patient still had a partial remission and not a complete remission would certainly be something that would have me concerned moving forward. In a situation where a patient has responded well but still has some residual disease, one could argue that maintenance rituximab is appropriate to try to prolong remission. But in a patient with clear evidence of residual disease, I start thinking about an alternative therapy pretty early on. Because they tend to relapse fairly quickly, which is what we saw in this case where the patient relapsed in less than a year.

Jonathon B. Cohen, MD, MS | Authors

Articles

Next Steps in Relapsed/Refractory Mantle Cell Lymphoma

BTK Inhibitors in MCL: Long-Term Safety & Efficacy Data

BTK Inhibitor Toxicities in Mantle Cell Lymphoma

Administration of BTK Inhibitors for Mantle Cell Lymphoma

Relapsed Mantle Cell Lymphoma Treatment Landscape

Initiating Therapy for Mantle Cell Lymphoma