Mitchell R. Smith, MD, PhD, recently shared both the more and less intensive treatment considerations he makes when treating patients with MCL and the major factors that influence them. Smith explained such considerations based on 2 case scenarios during a <em>Targeted Oncology</em> live case-based peer perspectives presentation.
Mitchell R. Smith, MD, PhD
While prognostic factors such as the mantle cell lymphoma international prognostic index (MIPI) and Ki-67 scores are important with regards to patient expectations, ECOG performance status and age are suggested to be the critical factors when determining treatment options for patients with mantle cell lymphoma (MCL).
Mitchell R. Smith, MD, PhD, recently shared both the more and less intensive treatment considerations he makes when treating patients with MCL and the major factors that influence them. Smith, a professor of medicine at George Washington University and an associate center director for clinical investigations in the Division of Hematology and Oncology at the George Washington Cancer Center, explained such considerations based on 2 case scenarios during aTargeted Oncologylive case-based peer perspectives presentation.
A 55-year-old male presented to his physician complaining of fatigue, unexplained weight loss and neck swelling. His past medical history was unremarkable, but a physical exam showed a bilateral cervical lymphadenopathy. Laboratory findings showed leukocytes at 9.0 109/L, hemoglobin levels at 9.8 g/dL, LDH levels at 520 U/L., and beta 2-microglobulin levels at 6.4 mg/L. Blood tests marked AST at 167 U/L and ALT at 202 U/L.
A CT and PET scan of the neck, check, abdomen, and pelvis marked a18F-FDG uptake and enlargement of the bilateral cervical lymph nodes (right, 4.6 cm; left, 3.1 cm) and mesenteric lymph node measuring 9.2 cm. A bone marrow biopsy showed no involvement. The patient was later diagnosed with Ann Arbor stage IIIB MCL.
TARGETED ONCOLOGY: What is the prognosis for this patient?
Smith: For the prognosis of MCL, we use the mantle cell lymphoma international prognostic index (MIPI), and this patient would be intermediate. This gives us some sense of PFS and OS, but it doesn't really change how we treat the patient. How we treat the patient is based more on age and [ECOG] performance status. If they are young and healthy, we give them more intensive therapy, often with autologous stem cell transplant (ASCT). If they are older or sicker, we go with less intensive therapy. The treatment [depends more on] what we think they can tolerate.
TARGETED ONCOLOGY: What are the choices for induction therapy for this patient?
Smith: Anyone under 60 or 65 is usually the cut off where we think about the more intensive therapy. Patients that are asymptomatic we can observe, but this patient is anemic, and yet otherwise reasonably healthy. So, we would give him a more intensive therapy.
There are several choices for intensive therapy, usually including an ASCT to consolidate the remission. Commonly used regimens include R-CHOP [rituximab (Rituxan) plus cyclophosphamide, doxorubicin (Adriamycin), vincristine, and prednisone]/R-DHAP [rituximab plus dexamethasone, high-dose cytarabine, and cisplatin]. This came out of the European studies showing that the regimen, followed by an ASCT, gave better results than R-CHOP followed by an ASCT.
The other commonly used treatment is called the Nordic regimen [rituximab plus alternating cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone and high-dose cytarabine], which is a similar dose intensity to R-CHOP alternating with a high dose of cytarabine (Cytarabine), then ASCT. They both have an R-CHOP and a high-dose AraC (cytarabine)-containing regimen alternating, followed by an ASCT.
The last regimen, which a lot of people have used but seems to be falling out of favor, is hyper-CVAD [hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, with methotrexate (Trexall) and cytarabine]. It also has a similar dose intensity to R-CHOP and a dose-intense cytarabine with methotrexate, but there have been issues with toxicity and stem cell collection [with this regimen], and it has fallen out of favor. I would say most people give the German regimen, R-CHOP/R-DHAP, or the Nordic regimen, followed by an ASCT.
TARGETED ONCOLOGY: What other factors do you consider when treating patients with MCL?
Smith: One factor that we don't talk about here is Ki-67, which is a measure of the proliferative rate. The higher it is, particularly over 30%, the worse the prognosis tends to be.
There are some newer molecular characteristic gene signature profiles, which may have some prognostic importance, and we will need to follow those. However, the choice of treatment is really based on whether the patient needs treatment and how intense of a treatment they might be able to tolerate.
TARGETED ONCOLOGY: This patient was treated with hyper-CVAD. Which therapy would you have chosen instead?
Smith: This treatment was in March 2013, so at that time many of us were using that regimen. Today, I tend to use the Nordic regimen. I'm not sure the cisplatin in R-DHAP adds much. Since the R-CHOP/R-DHAP regimen and the Nordic regimen are similar, and I don't think the cisplatin necessarily adds much, I like the Nordic regimen a little bit better and tend to use it more. But either one is fine.
At the Cleveland Clinic, where I was until recently, we were using standard R-CHOP, instead of the high-dose R-CHOP, with high-dose cytarabine as in the Nordic regime, and our results looked good. We think that might allow us to have a little more room to add additional drugs if we want to build on that.
Treatment was initiated with induction therapy R-hyper-CVAD and the patient achieved significant reduction in tumor burden. Consolidation therapy was given following an autologous stem cell transplant and the patient achieved complete remission.
TARGETED ONCOLOGY: Is transplant the goal for patients such as this one, who are young and fit?
Smith: As of today, the answer to that is generally yes, although the data to support that doesn't exist. The only randomized trial for ASCT was back in pre-rituximab and pre-intensive therapy days and it showed a benefit in PFS. The question must be asked again in the era of better treatments and newer agents, whether transplant adds anything. When you look at data based on who gets transplanted, it tends to be young and healthy patients, and they [tend] to do well anyway. The high MIPI patients don't do well even with transplants.
There is a study in Europe that is open and ongoing, which is going to ask whether transplant is necessary. They are randomizing patients to get R-CHOP/R-DHAP with ibrutinib (Imbruvica) and then randomizing them to get transplant or not. In this country, there is a trial that just opened [also aiming to answer this question]. If patients get whatever treatment the doctor wants to give them, and they've achieved no evidence of minimal residual disease by molecular studies, they are eligible to enroll in the trial and randomized to transplant or not. Outside of a clinical trial, today, if the patient is young and fit, I would say the general approach is to do the transplant to try to get the longest disease-free interval (DFI).
TARGETED ONCOLOGY: How frequently would you monitor treatment response for this patient?
Smith: Usually we will do it after cycle 3 and 6 of the induction therapy and once after the transplant is done. After that, there are no good rules. In many of the aggressive lymphomas, like diffuse large B-cell lymphoma, we do not monitor once the patient achieves a PET-negative complete response because they are either cured or not. In MCL we expect them to relapse, but it might be many years and if they relapse and they are asymptomatic, early identification may not matter and you might be getting frequent scans for years before they relapse. I think we've been getting fewer routine scans because we don't know what to do with the early relapse anyway. I would probably give them a couple times a year during the first few years, but I don't give them every 3 months. I depend more on symptoms to decide whether I should give scans.
We do see the patient every 3 months with bloodwork. Eventually, we may be looking at molecular studies to find early relapse, so there may be ways we can do this without frequent scans. Usually, it is listening to the patient and checking their bloodwork. If they feel fine and their bloodwork is normal, that is as good as you’re going to get in terms of not needing urgent treatment.
TARGETED ONCOLOGY: Would you use rituximab as maintenance therapy for this patient?
Smith: I would. That has been a bit of a question mark, but there is a couple of studies now, which show the benefit of rituximab in the post-transplant setting. In particular, one was published in theNew England Journal of Medicinenot long ago. It showed a clear benefit for PFS and a slight indication that maybe there was a benefit in OS, and the downside is pretty low.1So I tend to give rituximab maintenance. How often and for how long is an open question. In the post-transplant study, I believe it was for 3 years. In the original trial, which showed in the non-transplant setting, it was given until they relapsed. In a lot of settings, we do it for 2 years. I [tend to] give it for 2 to 3 years after transplant.
Four years later, the patient reported having symptoms of fatigue and weight loss. A CT and PET scan showed diffuse uptake of18F-FDG in the right lunch and mediastinal lymph nodes. A biopsy confirmed recurrent MCL.
TARGETED ONCOLOGY: What treatment options are still available for this patient who has achieved a long-term remission after induction chemotherapy and ASCT?
Smith: If you get through many years in remission, there is a wide range of options. Some people would do a second ASCT and hope to get another few disease-free years out of that. One could think about an allogeneic transplant, which at least holds out the possibility of cure. But, again, the downside is the risk of short term morbidity and mortality. Any of the chemotherapy regimens that we use, such as bendamustine (Treanda)-based regimens, are on the table. And there are many newer targeted agents, particularly ibrutinib (Imbruvica), which have shown excellent results in MCL.
The patient was switched to ibrutinib.
TARGETED ONCOLOGY: What is the rationale for using ibrutinib versus another targeted agent or chemotherapy? How do you typically use ibrutinib in MCL?
Smith: Ibrutinib is approved for patients with MCL that has been previously treated. The response rate is close to 70% and it is pretty durable, well over a year. It is an oral agent and well tolerated in most cases, easy for the patient.
The benefits of chemotherapy would be a shorter defined period, say 6 months of bendamustine and then hopefully some DFI. I think, given the high response rate, lack of toxicity, and lack of impact on your day-to-day life, ibrutinib is certainty a reasonable choice.
Having been through a transplant, some patients say it is easy and they don't mind going through it again, and some patients say they'll never go through it again. A lot depends on the patient as they come out and what they're interested in, what their lifestyle is like, and whether or not they want another short, intense therapy with the hopes of getting some disease-free time or if they mind taking pills everyday with the benefit of something that doesn't impact their life much.
There is a wide range of discussion and no right answer. The key is that, over time, many patients will get many of these things. The bottom line is that most patients will get all of these options over time, with the exception of an allogeneic transplant, which would probably be best earlier, but it is not done often with MCL today.
TARGETED ONCOLOGY: What type of response would you expect from this patient based on your personal experience with ibrutinib in this setting?
Smith: I found it to be pretty much as it is in the publications, about 2 out of 3 patients will have a very nice response and most patients tolerate it quite well. There is a little bit of a tendency for bleeding that you have to watch out for, and you should be careful. All studies did not allow patients to participate that were on coumadin (Warfarin) and I am very cautious if they are on other anticoagulation for other reasons. There is an incidence of atrial fibrillation and you can get into a cycle where you have atrial fibrillation and you need to anticoagulate, and now you’re stuck. But I think, overall, it is a well-tolerated drug and most patients do fine with it. The response rates are close to 2 out of 3 and tend to be durable. My experience is similar to the publications.
A 72-year-old male presented to his physician complaining of night sweats, intermittent fever (101-102) and fatigue lasting 2 months. His past medical history was remarkable for hypertension and was controlled on a beta-blocker and diuretic. A physical exam showed a markedly enlarged right supraclavicular lymph node and a palpable spleen.
Laboratory findings showed leukocytes at 6.73 X 109/L and LDH at 420 U/L. The patient underwent an excisional biopsy of the supraclavicular node, which showed the following immunophenotyping: IgD+. CD10-, CD19+, CD20+, CD22+, CD23-, and cyclin D1+. Cytogenetics were also noted at t(11;14)(q13;q32).
A CT and PET scan marked a diffuse18F-FDG uptake in the lymph nodes and spleen. The largest involved nodes were the right supraclavicular at 4.2 cm, the right mesenteric at 3.8 cm and the splenic hilar at 5.7 cm. His bone marrow was involved with MCL and the patient was later diagnosed with Ann Arbor IVB MCL.
TARGETED ONCOLOGY: What is the prognosis for this patient?
Smith: In this case, the patient is a little bit older with symptoms and needs to be treated. The prognosis varies from the previous case with the MIPI score and the K-i67.. I generally use the MIPI and Ki-67, that is combined and now called MIPI-C, either greater or less than 30%. That, right now, is probably our best prognostic indicator. As I mentioned before, it does not change the treatment, but it does give you some idea of what to expect going forward.
Given the bone marrow involvement, symptoms, and the elevated lactate dehydrogenase, his MIPI score is likely to be high. MIPI is very age dependent, so most of the older patients fall in the category of at least intermediate or high. This is not someone where you expect to get a 15-year median survival, it's going to be much shorter than that. Although, in the trials, even with these groups, the OS is improving with newer agents.
TARGETED ONCOLOGY: Why do you believe that risk stratification is important?
Smith: It doesn't really affect the treatment selection so much as what you expect and what you can give the patient to expect. Are you going to expect a long DFI with a late relapse or are you going to expect a more difficult disease that you will have to keep hammering at? At 72, some people would even think about a more intensive regimen. I think, especially if you thought the patient had a worse prognosis, even without clear evidence that a more intensive therapy is better, you might want to give the patient a more intensive regimen. That would be if you thought they had high-risk disease. Generally, I don’t do that, but some people choose to.
TARGETED ONCOLOGY: What are the choices for induction therapy for this patient?
Smith: I think most of us, in this age group, use bendamustine/rituximab. It has a very high response rate, reasonably durable responses and is well tolerated. You could also use R-CHOP with rituximab maintenance. R-CHOP by itself is not very good, but in the study which showed that rituximab maintenance was beneficial after R-CHOP.
There is a randomized trial where they substituted bortezomib (Velcade) for vincristine in R-CHOP and called it BR-CVP, and that was better than R-CHOP.2That is another regimen that some people use. That was given without rituximab maintenance, but we assume that rituximab maintenance will be beneficial after. You can defend many of these, but you are giving anthracyclines in an older patient population and the original study showed that bendamustine plus rituximab was better than R-CHOP. Based on that, and less toxicity, I think that bendamustine plus rituximab is still the treatment of choice based on its high response rate and good tolerability in these patients.
TARGETED ONCOLOGY:What are the factors that go into choosing the induction therapy?
Smith: Immunophenotyping is usually standard and just confirms the diagnosis of MCL. Cytogenetics in MCL and some of the molecular markers are a little bit behind where we are in chronic lymphocytic leukemia (CLL). Increasing data suggest, as in CLL, thatp53mutations or abnormalities of chromosome 17 are very important as poor prognostic indicators. We don't know yet whether there are specific treatments, such as ibrutinib, that might overcome that and might change our approach to those treatments.
Outside of the 17p deletion/p53question, I think that multiple cytogenetic abnormalities might give you concern, but don't tell you what to do. Right now, we are not at the point where we can select a treatment for MCL based on those molecular findings. Although we hope to be moving in that direction.
The patient was started on bendamustine plus rituximab. Follow-up PET and CT scans showed a partial response to upfront chemotherapy at 3 and 6 months.
TARGETED ONCOLOGY:After achieving only a partial response to induction therapy, what are the treatment options for this patient?
Smith: You have 2 choices at this point. One is to say that you have had a partial response and you want to try to maintain it as long as possible. I would then give rituximab maintenance. The data on rituximab maintenance after bendamustine plus rituximab is not very solid, it is better after R-CHOP and after the transplant.
The concern is that this patient had a relatively high-risk disease, it was symptomatic, and he hasn't had a good response to our best treatment. This might be a time to change the treatment to something entirely different. That is what was done in this case, we wanted to increase the depth of response. Then the question is whether or not to switch to a different chemotherapy regimen and cytotoxic, like R-CHOP, which is likely to have some benefit. Or you could decide that you've shown that his cells are resistant to standard chemotherapy in the form of bendamustine and is probably going to be resistant to other chemotherapies. You could then switch to a targeted agent such as ibrutinib, which was done in this case.
TARGETED ONCOLOGY: What is the rationale for switching rather than consolidating with rituximab maintenance?
Smith: If the patient had a good response, was asymptomatic, and you were happy with keeping him at that level, then I think rituximab maintenance would be a reasonable option. You wouldn't lose anything if you started him on rituximab maintenance and, over the next few months, he started to progress. You would then have your answer and switch to a new agent. There is no right or wrong. It depends on the patient in front of you and what your sense is, whether you think that rituximab maintenance is likely to maintain him at this level and that the level is ok. If you think the disease is not quite stable at that partial response, you may want to use this as a new opportunity to get a new drug in.
Treatment was discontinued and the patient was started on ibrutinib.
TARGETED ONCOLOGY: What would be done if the patient developed atrial fibrillation on ibrutinib?
Smith: Atrial fibrillation is not uncommon as we get older, but it is clear that ibrutinib does raise the risk of that. Sometimes atrial fibrillation is not that much of a problem and can be easily controlled with medication. But it often prompts anticoagulation. So you will need medication to control the atrial fibrillation, and now you need to be anticoagulated, and now you’re on ibrutinib and anticoagulation. Now you not only have atrial fibrillation, but also the concern about bleeding risk. That makes the clinical management a lot more complicated.
There is another BTK inhibitor called acalabrutinib (Calquence), which was fast-tracked and [recently approved for previously treated MCL]. Early data suggest that it might not have the same atrial fibrillation risk and possibly not the bleeding risk. That drug may change our approach, and how we fit that in with ibrutinib remains to be seen.
There are a number of algorithms for how you approach atrial fibrillation. We normally want to get our cardiologist involved to tell us what the risk is, if we need anticoagulation and what medicine we need to control it. We need to be concerned about drug interactions with ibrutinib to make sure we have don’t have to adjust the ibrutinib and/or the antiarrhythmics. I have a lot of patients on ibrutinib with atrial fibrillation and if they are doing well you can continue them on the treatment if the atrial fibrillation is well controlled and the anticoagulation is managed.
TARGETED ONCOLOGY: What other treatment options are available or are on the horizon for patients with MCL?
Smith: There are other drugs that are approved for MCL, such as bortezomib, which I mentioned with BR-CAP frontline, but is approved for the relapsed setting. We should also mention lenalidomide (Revlimid) because the lenalidomide/rituximab combination is very active and many patients, third line or later, will get that combination. There is a small upfront trial, so I think people should be aware that lenalidomide is active. Also, acalabrutinib is now approved. It is given twice daily, instead of once daily, and that always brings up the question of compliance and whether or not patients will be willing to take the drug twice a day. We are anxious to see, in the real world, whether acalabrutinib really does not have the atrial fibrillation and bleeding issues that ibrutinib has. That is something we will have to keep an eye on.