During a <em>Targeted Oncology </em>live case-based peer perspectives presentation, Jonathon B. Cohen, MD, MS, explained to a group of physicians the treatment considerations and decisions he makes when seeing a patient with mantle cell lymphoma in the clinic.
Jonathon B. Cohen, MD
During aTargeted Oncologylive case-based peer perspectives presentation, Jonathon B. Cohen, MD, MS, explained to a group of physicians the treatment considerations and decisions he makes when seeing a patient with mantle cell lymphoma (MCL) in the clinic. Cohen, an assistant professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine, and medical director of Infusion Services at Winship Cancer Institute of Emory University in Atlanta, Georgia, discussed treatment options in relation to a case scenario of a patient with newly diagnosed MCL.
A 55-year-old man presented to his physician complaining of fatigue, unexplained weight loss, and neck swelling. His past medical history was unremarkable. A physical exam showed bilateral cervical lymphadenopathy. Laboratory findings showed leukocyte count of 9.0 x 109/L; hemoglobin, 9.8 g/dL, lactate dehydrogenase (LDH), 200 U/L; beta2-microglobulin, 6.4 mg/L.
An excisional biopsy of the right cervical node revealed IgM+, CD5+,CD10, CD19+, CD20+, CD22+, CD23–, cyclin D1+, and t(11;14) (q13;q32) cytogenetics. CT/PET imaging of the neck, chest, abdomen, and pelvis showed marked18F-FDG uptake and enlargement of the bilateral cervical lymph nodes (right, 4.6 cm; left, 3.1 cm) and mesenteric lymph node (9.2 cm). A biopsy showed the bone marrow was not involved. He was diagnosed with MCL, Ann Arbor stage III. This patient was considered intermediate risk, with a Mantle Cell Lymphoma International Prognostic Index (MIPI) score of 5.8.
What is the prognosis for this patient?
As one might decide to do, you can calculate the MIPI score, so we have the International Prognostic Index (IPI) which we typically use for diffuse large B-cell lymphoma, but for MCL, there is an MCL IPI, which incorporates age, ECOG performance status, LDH, as well as the white blood cell count. One of the first things that will pop out is that, unfortunately, it's not just a 1-2-3-4 calculation. In cases where I have a patient where I'm going to think about calculating this, I typically will go to the internet calculator where you can basically type things in and it spits it out. Patients can be divided into low, intermediate, or high risk. This patient was intermediate risk.
Similar to the IPI score for Hodgkin lymphoma, MIPI is valuable as a prognostic tool. It hasn't been utilized frequently to inform therapy decisions. Some patients get into the nitty gritty and want to know what [is their] prognosis and what do [I] expect for [them]. In those cases, this may be something we can discuss. For patients who may want this type of information, I don't know if it's necessarily critical with regards to treatment decision making. There has been integration of the MIPI with Ki-67 to develop the MIPI-c. One of the things that is most important prognostically for MCL is Ki-67. We know about that for large cell lymphoma and when we see it's high, it's concerning. But in MCL, through mostly European studies, we've seen that Ki-67 greater than 30% is associated with an inferior outcome. Those patients that have a high MIPI score and an elevated Ki-67, the median overall survival (OS) is quite poor, it's less than 2 years, whereas the median OS for the patients that are low risk in these studies was 9.4 years. Do I calculate this on every single patient? Not necessarily, but it is something to think about as I'm seeing patients.
What treatment approach would you take for this patient?
This is an otherwise healthy person, 55 years old, who has advanced stage MCL with reasonable disease burden. Let's say the Ki-67 is 40%, so it's moderately elevated. In most cases, if you have a patient that's young like this and you're thinking about [going for] a transplant, I think the high-dose cytarabine is the most important component. There are increasing data that bendamustine/rituximab (Rituxan; BR) can be given prior to transplant, and there actually is going to be an intergroup study looking at a couple of different arms, 1 of which will be BR prior to transplant. Outside of that setting, most people would try to give high-dose cytarabine. At Emory, more often than not, many of us will use hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone). I think for a person under the age of 60, I tend to feel pretty comfortable using it. It's not clear though that that's necessarily better than using the R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone) or R-DHAP (rituximab, dexamethasone, cisplatin, and cytarabine) regimens, or the other one we often will use is the NORDIC regimen, which is sort of an R-Maxi-CHOP (dose-intensified CHOP) alternating with rituximab and high-dose cytarabine. I view these as generally similar. I will say that if I have somebody that has really high-risk pathologic features, especially if they're young but they have really aggressive-behaving disease, I tend to still move toward R-hyper-CVAD in that setting. I think that's reasonable.
A lot of my patients I see are in their mid-60s, where I am a little bit more nervous about R-hyper-CVAD and I will end up using the NORDIC regimen. I think that R-CHOP/R-DHAP is a very good therapy. We, at least at our center, have had significant issues with renal insufficiency. One alternative that has been reported is that you can substitute the cisplatin with carboplatin or oxaliplatin and that's something we've had a little bit of experience with as well. Unfortunately, I'm not here to say which one is the right one, I think any of them are useful.
Is there a role for stem cell transplant in this case? Is transplant the goal for all younger, fit patients?
I think right now in March of 2019, for a young patient with more typical standard risk features like this patient, consolidation with an auto transplant is still commonly utilized if the patient ultimately responds and is able to go to transplant. There is a study that is currently ongoing that we have at Emory that is a national study looking at assessing minimal residual disease (MRD) for patients with MCL who complete induction therapy. If they're MRD negative they get randomized to either go straight to rituximab maintenance or go to a transplant [NCT03267433]. I think it's an important question because the only randomized study looking at transplant was an R-CHOP plus transplant versus not, so it was in a different era.
There is this possibility that especially MRD-negative patients may enjoy a long remission without transplant. You might not be surprised to know that it's been a little bit of a challenge to enroll patients, because it's such a difference. You're talking about either a month in the hospital with a transplant, or just going to rituximab maintenance. People often have different feelings about if they want to be aggressive. We've had a couple of patients that presented, and they say they don't want the transplant, and others that say they definitely want the transplant. I think it's sort of an open question at this point, given some of the newer therapies that we have. Right now, if I see a patient like this, I would definitely try to get them to transplant.
The patient received an aggressive cytarabine induction regimen and achieved significant reduction in his tumor burden. Consolidation with autologous stem cell transplant resulted in a complete remission.
Would you use rituximab maintenance in this case? Do you consider it for all of your patients with MCL?
There are a number of different scenarios where you would think about rituximab maintenance in MCL. The randomized trials where it has probably been the most associated with improvement were after autologous stem cell transplant on the LyMA study. This was in patients primarily that just got RDHAP and then went to transplant. You could argue if you get R-hyper-CVAD, which is a more variable therapy and maybe a longer induction, do they still need it? That's not known. These are patients that went on to receive rituximab maintenance after R-DHAP, they did better. For older patients that received R-CHOP, which is not a ton of patients at this point, that's where there has been randomized data that suggest it's improved. After BR, it's much less clear. There was a small randomized trial, which looked at rituximab maintenance after BR and saw no benefit. We've looked at it in a national consortium that we put together. We actually are submitting the abstract for the Lugano meeting, and it looks like, at least in the United States in this retrospective cohort, that for patients that respond, especially those that have a partial response, there may be a benefit to giving rituximab maintenance after BR. That's still definitely an area that's unclear. After transplant, it does appear to provide some benefit.
Is there a role for MRD assessment?
I think that what it looks like is MRD does make a difference for MCL, and so there have been a number of studies that have looked at it post-transplant and pre-transplant. One of the challenges with MRD, at least measured outside of an investigational setting, is that there is some question about when you assess it, what you should do if it's positive, and how it should be assessed. Right now for a standard patient, I typically don't assess it, unless they're going to enroll in a clinical trial or there's something that you're going to do with it. I at least haven't had anyone that has come asking for it, but I think that there likely is something to it in MCL, but it's not exactly clear when it should be assessed.
Four years after diagnosis, the patient reported having symptoms of fatigue and weight loss. PET/CT showed diffuse uptake of18F-FDG in the right lung and mediastinal lymph nodes. Biopsy confirmed recurrent MCL.
What treatment options are available for this patient who has achieved a long-term remission after induction chemotherapy and stem cell transplant?
Ibrutinib (Imbruvica) is frequently used here, but it's not the only option. In this particular case, the patient was started on ibrutinib. The other therapy that I would think about sometimes here is actually BR if they got transplant upfront, it's a very effective second-line therapy. The other regimen I sometimes will look at is rituximab/lenalidomide (Revlimid), even though it's not FDA approved in that setting, it can also be very effective. But, in most patients at first relapse if they're eligible for it, I would be thinking about a BTK inhibitor.
The patient was started on therapy with ibrutinib.
What is the rationale for using ibrutinib versus another targeted therapy or chemotherapy?
In my mind at least, this really comes down to a patient-specific discussion. Some people don't like the idea of being on chronic therapy and you can potentially treat them with chemotherapy. Some people have atrial fibrillation, not that that's an absolute contraindication, but maybe if there's an alternative you might do that as well.
A  paper [Rituximab after Autologous Stem-Cell Transplantation in Mantle-Cell Lymphoma] highlighted the use of rituximab after autologous stem cell transplant. This was actually a pretty remarkable finding. I think it surprised a lot of people that there was such a marked difference. As many of you I'm sure know, rituximab maintenance after therapy in follicular lymphoma and in other settings has been associated with improved progression-free survival (PFS), but we hadn't really seen an OS benefit. In this particular study, they did see a marked improvement both in PFS and OS using rituximab. I found this to be relatively convincing data. Now having said that, if I have somebody that doesn't want to do it, or they get started and they have a lot of trouble with it, I have a fairly low threshold to stop it. It's not clear that they actually have to get the full couple of years, but I think it's certainly worth the consideration.
Le Gouill S, Thieblemont L, Oberic A, 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.