Medical Oncologist at Dana-Farber Cancer Institute/Brigham and Women’s Cancer Center’s Adult Lymphoma Program
Could you briefly describe MCL?
Mantle cell lymphoma (MCL) is a disease which falls relatively halfway between slow-growing lymphomas and fast-growing lymphomas. It is a disease that tends to present in multiple different areas (e.g., lymph nodes, bone marrow, spleen, blood, and sometimes in the gastrointestinal tract). When people look online to read about this disease, the first thing they inevitably read is that MCL is not curable with standard chemotherapy. That is true, although there are a number of very effective treatments and patients often do live a long time with this disease.
The vast majority of patients with MCL will present with what we call advanced-stage disease:Stage III or IV. With Stage I, patients present with one lymph node area involved. In Stage II, there are two or more areas involved (either all in the neck and chest or all in the abdomen and pelvis). Stage III is essentially disseminated lymph node involvement (above and below the diaphragm, which cuts the body in half). Stage IV means that the bone marrow or any non-lymph node is involved; the majority of patients will present with bone marrow involvement.
At the time of presentation, one-third to one-half of patients will have what we call B symptoms, namely fevers, drenching night sweats, or unexplained weight loss. A fair number of patients will present with abnormal lymph nodes or abnormality on blood tests (i.e., sometimes you’ll see lymphoma in the blood). In addition, patients can sometimes be diagnosed at the time of the colonoscopy screening when small tiny polyps are seen throughout the colon.
How common is MCL?
MCL is a rare subtype of non-Hodgkin lymphoma (NHL). It comprises six-seven% of all the NHL cases seen. In the United States, there are about 70,000 new cases of NHL each year. It tends to affect men much more prominently than women for some reason, and people who present are typically diagnosed in their mid-60s.
How is MCL typically treated?
There are really a number of different options. The way we typically think about treating patients with mantle cell is based on their age. For patients younger than 70 years old (or 65 years; some physicians use a cutoff at 60 years) who do not have a lot of other medical comorbidities, we typically treat fairly aggressively, with initial chemotherapy followed up with high-dose chemotherapy and what we call autologous stem cell rescue. Autologous stem cell transplant allows us to significantly intensify the dose of chemotherapy that we can give with the goal of eradicating all lymphoma cells.
For autologous stem cell transplant, stem cells are collected from the patient’s blood. The stem cells are bone marrow stem cells, the cells that make all the blood cells — the white cells that fight infection, the red cells that carry oxygen, and the platelets that prevent bleeding. The cells collected are stored away, the patient is given high-dose chemotherapy, and then the stem cells are reinfused into the patient. Therefore, the stem cells have not been exposed to that high-dose chemotherapy, which would have significantly damaged the stem cells, and patient’s blood cell counts would recover.
It has been shown that doing stem cell transplant after initial standard chemotherapy results in much better outcomes (i.e., people staying in remission significantly longer than using standard chemotherapy alone).
In addition, when younger patients who have had their disease recur after autologous stem cell transplant, using donor stem cell transplant (or allogeneic stem cell transplant) is an option that can potentially offer the possibility of long-term control of the disease or essentially curing the disease. It has a lot of potential toxicities, although those are getting better over time as we are getting better at managing what is called graft-versus-host disease. Any time you replace a patient’s stem cells with a donor’s stem cells, the donor cells know that the body of the recipient is different from where they normally live and can cause difficulty with different organ systems in the recipient.
Another treatment option is to use highly aggressive chemotherapy, such as the rituximab (Rituxan) plus cyclophosphamide, vincristine, doxorubicin (Adriamycin), and dexamethasone (hyper-CVAD) regimen. They have shown very good outcomes using this chemotherapy alone, not necessarily followed by an autologous stem cell transplant because it delivers the intensive chemotherapy upfront.
The types of chemotherapy that are used before stem cell transplant vary around the world. In the United States, we use a lot of rituximab plus cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (CHOP), a five-drug chemotherapy regimen that is used in other types of aggressive lymphoma. In Scandinavia, they use a more intensified regimen called the Nordic regimen. And this is followed with high-dose chemotherapy and autologous stem cell rescue, which results in a very nice long remission.
The French use rituximab-CHOP (R-CHOP) plus a different chemotherapy regimen that they alternate with called RDHAP (rituximab, dexamethasone, cytarabine, cisplatin). These are all good options.
For patients who are older than 65 or 70 years old or patients who have other significant medical problems, we tend to use a little bit more gentle chemotherapy because it can be difficult to collect stem cells in older patients, and stem cell transplant could have more complications in older patients.
One option is to use bendamustine (Treanda)/rituximab. This regimen was recently compared with R-CHOP in a study from Germany, and patients stayed in remission longer when they received bendamustine with rituximab. It is a very well-tolerated combination.
There was also recently a study from Europe that looked at R-CHOP versus a different chemotherapy regimen, using Fludara (fludarabine)-based therapy; and they found that R-CHOP was better tolerated than fludarabine plus rituximab plus cyclophosphamide (Cytoxan). When they followed this up with maintenance rituximab, essentially giving a prolonged course of rituximab, compared with giving a drug called interferon that really isn’t used much in the United States, they found some very nice results with maintenance rituximab. Patients were given a dose every two months after they had completed their initial chemotherapy, and the percentage of patients doing well at four and five years looked very, very good. Bendamustine plus rituximab is an option. There are a number of other chemotherapy regimens that are active.
There are two other subsets of patients that I should mention. Occasionally patients with MCL will present with localized disease (i.e., Stage I or Stage II disease). Again, it is a very uncommon presentation, but for those patients, using combination chemotherapy and radiation or radiation alone has resulted in some very long-term remissions; and possibly the disease may not come back. It is hard to know for sure. You have to follow patients for a long time, and that is how we would manage those patients.
There is also a subset of patients with MCL who tend to have more slow-growing disease. And one of the prognostic indicators we look at in terms of how someone’s disease is going to act is by looking under the microscope and seeing how quickly the cells are dividing; it is called the Ki‑67 fraction. When the Ki‑67 fraction is low, patients tend to have more slow-growing or indolent forms of the disease.
There is a subset of patients who present with disease in the blood, often with an enlarged spleen, but without a lot of lymph node involvement. These patients can have a very slow-moving course, and it is certainly a very reasonable alternative to observe these patients rather than treat them. There have been some data in the United States suggesting that there is no disadvantage in terms of how people live if you follow them initially and then treat them at the time they need treatment.
This is how we treat patients with slow-growing lymphomas. The reason you would treat someone is if they had symptoms that related to lymphoma, if their blood counts were falling because the bone marrow was being compromised by the lymphoma or they were having a big spleen or big lymph nodes, then we would initiate treatment.
Do you talk to patients about enrolling in a clinical trial?
In terms of the optimal initial treatment, there are now a lot of, what we call randomized clinical trials, meaning we take a group of patients with similar characteristics and assign them to two treatment options and then compare the results of treatment with those options side-by-side to see which is best.
We really encourage people to participate in clinical trials, given that there are a lot of potential good options for treating patients. We would really like to establish which treatments provide the optimal outcome.
There is currently a randomized study in the United States that all of the Cancer Cooperative Groups are participating in, comparing hyper-CVAD with a newer regimen using a drug called bendamustine. It was recently approved in the United States for use in lymphoma and has been available in Europe for more than 30 years; and it is a very, very active drug.
In the trial, they are comparing rituximab plus bendamustine versus this aggressive regimen called R-hyper-CVAD. Patients are randomized to one of those two arms and then followed up with a stem cell transplant to try to identify which is really the optimal initial chemotherapy.
Patients will then be randomly assigned to receive rituximab alone or rituximab plus lenalidomide (Revlimid), which is a fairly new drug approved for other malignancies and appears to have very good activity. So we look forward to seeing the results of that study because it should help to identify which might be the best initial regimen for older patients.
Right now there is also an intergroup study in the United States comparing two different initial chemotherapy regimens, bendamustine plus rituximab with or without a drug called bortezomib (Velcade), a proteasome inhibitor (proteasome is active in patients with MCL).
What is on the horizon for MCL research?
There are a lot of new drugs being investigated. There is a drug called ibrutinib, which is a Bruton’s tyrosine kinase (BTK) inhibitor that has been studied as an oral single-agent in MCL. It has very high response rates and is very well tolerated. There is another drug that used to be called CAL-101 and it is now called GS-1101. The agent is from a class of drugs called the phospoinositide-3 kinase (PI3K) inhibitors. This is another drug that is very well tolerated and has very good response rates. Bortezomib, the proteasome inhibitor I mentioned, is an approved drug for MCL. There is a related drug called carfilzomib (Kypoli) that is being investigated in clinical trials And was recently approved by the United States Food and Drug Administration for the treatment of patients with multiple myeloma.
There is a class of drugs called the mTOR inhibitors, which includes everolimus (Afinitor). This drug is active in MCL, and there are some combinations of mTOR inhibitors and PI3K inhibitors that are currently being studied.
There are a number of new antibodies, like rituximab, but that work slightly differently that are being investigated.
There are a lot of clinical trials in stem cell transplant trying to identify better initial chemotherapy regimens before the stem cell transplant happens and trying to better manage graft-versus-host disease.
How are you involved with the Lymphoma Research Foundation (LRF) and why would you recommend a patient become involved with them?
LRF is just an amazing organization. I first became involved with the LRF locally. I work at Dana-Farber Cancer Institute, and every year we conduct a patient forum whereby a number of us will speak on different topics and meet with smaller patient groups around specific disease topics.
I was just very impressed by the organization. They seamlessly organized 300-400 patients to participate in the Massachussetts Lymphoma Workshop, and they just have so many resources available for patients and caregivers.
Over the past year they established another really great program in New England: Lymphoma Rounds. They organized lymphoma specialists from all of New England, including Dartmouth, the University of Vermont, Brown University, the University of Massachusetts, and physicians from all the Boston programs. Physicians get together, each meeting with a different lead institution. The lead institution will present three cases followed by an open discussion among the lymphoma doctors. It is really great way to meet colleagues who are interested in lymphoma, talk about new areas of research, and discuss difficult cases. I have been very impressed by that.
LRF also gives grant funding for new and established investigators, which is critical for developing new and better treatments. LRF is just an incredibly well run organization from my perspective. They are so organized and have so much to offer to both patients and physicians.
Updated: August 15, 2012