Cohen Considers the Role of Transplant in "Modern Era" MCL

Jonathon B. Cohen, MD, MS

During a recentTargeted Oncologylive case-based peer perspectives dinner, Jonathon B. Cohen, MD, MS, discussed his treatment considerations and decisions for treating patients with mantle cell lymphoma (MCL). Cohen, an assistant professor in the Department of Hematology and Medical Oncology and medical director of infusion services at Emory University School of Medicine, made these decisions based on a case scenario of a patient with advanced-stage MCL presented at the event.

Case

A 55-year-old man presented to his physician complaining of fatigue, unexplained weight loss, and neck swelling; past medical history was unremarkable. His physical exam showed bilateral cervical lymphadenopathy and his laboratory findings were notable for the following: leukocytes: 9.0 x 10⁹/L; hemoglobin (Hb): 9.8 g/dL; lactase dehydrogenase (LDH): 520 U/L;β-2-microglobulin (B2M): 6.4 mg/L

He underwent an excisional biopsy of the right cervical node, where his immunophenotyping showed IgM+, CD5+, CD10-, CD19+, CD20+, CD22+, CD23-, cyclin D1+. Additionally, cytogenetics revealed t(11;14), (q13;q32).

A CT/PET imaging of the neck, chest, abdomen, and pelvis showed marked 18F-fluorodeoxyglucose (18F-FDG) uptake and enlargement of bilateral cervical lymph nodes (right, 4.6 cm; left, 3.1 cm) and mesenteric lymph node (9.2 cm). His bone marrow biopsy was not involved.

Based on these findings, he was diagnosed with MCL, Ann Arbor stage III.

What are your general impressions of this patient?

This is a 55-year-old man who presented to his physician with fatigue, unexplained weight less, and neck swelling. He is otherwise healthy but has a palpable disease on exam. His counts reveal some anemia and elevated LDH. He had an excisional biopsy, which was CD5+, CD23-, and cyclin D1+. This is a classic MCL immunophenotyping. He also had diffuse adenopathy and, interestingly, his bone marrow was negative. More often than not, marrow is positive in MCL, but not always. This is still an advanced-stage MCL.

What is the prognosis of this patient?

In MCL, there is a prognostic index. Historically, we have the International Prognostic Index (IPI) for diffuse large B-cell lymphoma, however, there is also a MCL IPI. One of the challenges is that the calculation is not particularly easy. It includes age, ECOG performance status, LDH, and white blood cell count (WBC). It also includes logarithms and decimals. This is a highly prognostic index, but it is not always easy to use in practice. Typically, if I am going to calculate it, I will calculate it online.

With this scoring, patients get divided into low-, intermediate-, or high-risk disease. These have been associated with overall survival (OS). The high-risk patients tend to have an OS of less than 3 years, whereas the intermediate- and low-risk patients tend to have a much longer OS. About 30% of patients have high-risk disease.

The other prognostic marker that we try to use is the Ki-67 index. The same group that developed the MIPI score also developed the combined-MIPI score, which includes the low-, intermediate-, or high-risk MIPI score, as well as Ki-67 using a cutoff of 30%.

Again, what we see is that those patients that have a high Ki-67 and a high MIPI have an OS of only 1.8 years. Those are patients that do not do well. Whereas those patients who have a low MIPI and a low Ki-67 have a median OS of almost 10 years.

What we've seen in our own center—we've also looked at this around the United States—is that the median OS for all-comers is definitely moving upwards. We did one series where it was a median of 11 year. Granted those were all patients who came to 1 of 5 academic centers. There are likely patients that you may see out in the community who are either not able to come or are too sick. It is not always a perfect example, but by using these clinical factors and the Ki-67 we can differentiate patients. This patient’s MIPI score was a 5.8, which puts him in the intermediate group. Historically, these patients tend have an OS of 3 to 5 years.

What general approach would you take for this patient?

This is a 55-year-old, healthy man with advanced-stage MCL. In general, the way I think about MCL is through 3 primary approaches. One option—which I think is a lot more viable than it used to be—is that you can observe some of these patients. There are some patients who come in who are referred from their primary care physician for a WBC of 12,000 with lymphocyte predominance and you think that it is CLL, but when you do the workup it turns out to be MCL. They have no other lymph nodes or just some mild asymptomatic splenomegaly—or even patients who have small lymph nodes who are asymptomatic—many of these patients can be observed.

There was an initial study of Cornell where they looked at their own patients and found that there were a handful of patients that they had observed without treatment who were asymptomatic at the time of diagnosis. We've done a couple of similar projects looking nationwide through the national cancer database. At Emory, we also did a 5-center study looking at it. It looks like there is this group of patients who have low tumor burden—similar to a patient with follicular lymphoma—who you would say have a low tumor burden that you could potentially observe.

However, if you have someone like this who is more symptomatic, the most aggressive approach right now would be to use a cytarabine-based induction therapy, such as cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, and dexamethasone (hyper-CVAD). There is another regimen known as the Nordic regimen, which alternates rituximab (Rituxan), cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone (R-CHOP) with rituximab high-side cytarabine. It should be some sort of cytarabine-based induction followed by a stem cell transplant. That is our typical approach at Emory and it is most commonly what is done throughout the United States for fit patients with active disease.

For patients who are not fit or who are not transplant candidates, we often will use a less aggressive regimen such as bendamustine (Treanda) plus rituximab (BR). This is also reasonable. There is also a study from Cornell looking at rituximab and lenalidomide (Revlimid), which is an oral therapy. This also looks pretty promising in upfront MCL. The problem with that approach is that it requires chronic therapy, but if you have a patient who is trying to avoid chemotherapy, it is a consideration.

Is there a role for stem cell transplant in this case? Is transplant the goal for all younger, fit patients?

There is a study that Emory is participating in right now trying to reevaluate the role of stem cell transplant in MCL (NCT03267433). It is an ECOG study where patients can get any induction therapy and then have a minimum residual disease (MRD) assessment at the end of induction. If they are MRD-negative, they are randomized to either transplant followed by rituximab maintenance or just rituximab maintenance.

The rationale behind this is that when the initial transplant studies came out, some patients had CHOP and others had R-CHOP, and then they were randomized to transplant or not. We now know that this is probably not adequate therapy for MCL. Now, in the modern era, there is an interest to see if transplant is still required for these patients. It is conceivable within the next few years that the approach may change. If I have a patient who I am really worried about, I have not been offering them the study and I think that transplant is important. But, for other patients, we were able to get them on the study. The only place where that is a little bit different is for patients with aTP53mutation. Those patients have not historically done well with transplant and there has now been a couple of series looking at that.

The patient received an aggressive cytarabine induction regimen and achieved significant reduction in tumor burden. Consolidation with autologous stem cell transplant resulted in complete remission.

Would you use rituximab maintenance in this case? Do you consider it for all of your patients with MCL?

Rituximab maintenance has been assessed for MCL in a couple of different settings. In a randomized trial, post-transplant, patients received rituximab, dexamethasone, cytarabine, and cisplatin (R-DHAP) as induction therapy, went to transplant, and then were randomized to maintenance versus no maintenance.¹There was an actual OS benefit for patients who received rituximab. Therefore, for all of my transplant patients, I have traditionally been offering it. Historically, rituximab maintenance, although it has often prolonged PFS, it has not always prolonged OS. So, when these data came out they were very compelling.

For the non-transplant patients, there is a randomized study using R-CHOP as the backbone that shows that if you have a non-transplant patient that gets R-CHOP, rituximab maintenance is of benefit. There was a smaller study looking at BR as the backbone, which did not show a benefit. So, for the non-transplant patient, it is still up in the air.

Do you have an age cutoff for patients who you would consider for stem cell transplant?

I just had a patient who is 76-years-old who I just transplanted. However, I was just in Belgium talking about MCL and they have it set up where if you are over a certain age you cannot do it. I was nervous about the 76-year-old, but if you were to see him walking down the hall, he looked like he was 61 or 62 years old, and he did beautifully. He developed C. difficile infection and we treated him. He got over it without any problem. He was walking the whole time and was discharged on day 12 or 13 and has gone back to his referring doctor now and is doing great. He is the oldest person I've ever transplanted. Of note, we usually do a lower dose of melphalan for those patients.

Four years of diagnosis, the patient reported having symptoms of fatigue and weight loss. His PET/CT showed diffuse uptake of 18F-FDG in the right lung and mediastinal lymph nodes and a biopsy-confirmed recurrent MCL. The patient was started on therapy with ibrutinib (Imbruvica).

What treatment options are available for this patient who achieved a long-term remission after induction chemotherapy and stem cell transplant?

This patient ended up getting a stem cell transplant and then 4 years later he developed fatigue and weight loss. There was a PET scan done, which showed some new uptake. With biopsy it was confirmed recurrent MCL.

At this point, you have the Bruton’s tyrosine kinase (BTK) inhibitors. There are several other FDA-approved therapies. Bortezomib (Velcade) is FDA approved in this setting. Lenalidomide as a single-agent is FDA approved for patients who have had bortezomib already, although often you can get it off-label. If I'm going to use lenalidomide in this setting I would do it in combination with rituximab. Most people in the first relapse would use ibrutinib. The other regimen that probably doesn't get appreciated is BR. It is very effective for relapsed MCL. If you have a patient who may not necessarily want to do chronic therapy because they are young, or they don't have good drug coverage, BR has good data for long-term remission for patients with MCL.

What is the rationale for using ibrutinib versus another targeted agent or chemotherapy?

I don't have any reason to say that ibrutinib is necessarily better than acalabrutinib (Calquence) or vice versa. It may be less toxic, and I think with time we will find out. One of the challenges is that for ibrutinib there are a lot of toxicities that developed which were not expected [during the study]. Everyone went on the study and then some developed atrial fibrillation and some developed bleeding. Whereas, when acalabrutinib was coming along, if you had a patient with atrial fibrillation, you may not have put them on that study. It may have been a lower-risk group of patients. Personally, I think they are generally equivalent in efficacy. The acalabrutinib may end up being better tolerated, we will have to see how that pans out. However, all things being equal, I have had more experience with ibrutinib and that is typically what I do. But there is nothing wrong with acalabrutinib. They are both good drugs and I will often have our pharmacist run both to see if 1 is cheaper than the other.

One of the other challenges is that patients who progress on ibrutinib have a very poor OS and that has been some of the concerns, although some of that is because it was probably being used later in treatment. So, by the time patients got it and progressed on it, they had already had 4 or 5 other treatments. I usually use it as my first salvage therapy.

What type of response would you expect based on your own personal experience with ibrutinib in this setting?

One of the things with ibrutinib is that the complete response (CR) rate is actually modest, it is about 20%, but the response rate is a lot higher.²It is roughly two-thirds of patients who will respond. Often patients will have a prolonged partial response (PR). They may never actually achieve a CR, but they may stay in PR for a couple of years. I think it is important when you are counseling with our patients to say: "You may not have everything resolved entirely, but if you have near resolution of your lymph nodes and you are feeling well and tolerating, that is something to be pretty happy with.

References:

1. Le Gouill S, Thieblemont C, Oberic L, et al. Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma.N Engl J Med. 2017;377(13):1250-1260. doi: 10.1056/NEJMoa1701769.
2. Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma.N Engl J Med.2013;369(6):507-516.