Assistant Professor of Medicine; Division of Hematology and Oncology; New York-Presbyterian Hospital/Weill Cornell Medicine
Would you briefly describe mantle cell lymphoma?
Mantle cell lymphoma (MCL) is a cancer of the white blood cells that, during the process of their normal maturation, underwent a series of mutations which took them down the wrong path. One of those mutations resulted in the loss of control of the cell cycle. Under normal circumstances, a white blood cell might grow for a little while, stop growing and then decide whether or not it's really necessary to fight an infection; only under certain circumstances would it then progress and start dividing.
In MCL there is an acquired genetic mutation that results in the overexpression of a gene called cyclin D1. The constant presence of cyclin D1 essentially tells cells to synthesize new deoxyribonucleic acid (also referred to as DNA) and divide in the absence of any external stimulus telling them to do that. Over time, these cells grow and divide more rapidly and accumulate due to that cell division.
How common is MCL?
MCL is not a very common disease and is often classified as a rare, or orphan, disease. MCL represents about five percent of all non-Hodgkin lymphoma cases in the United States and, on average, approximately 5,000 people are diagnosed with MCL each year. People with MCL are living longer and the prevalence of people with MCL is increasing despite low number of newly diagnosed people each year.
How is MCL typically treated?
You could ask that question to many different MCL experts and get many different responses. One thing everyone agrees on is there is no standard treatment for MCL as it is a remarkably diverse type of lymphoma. In some cases, MCL might behave very indolently (grow remarkably slowly or not grow at all), while in other cases, MCL might grow very quickly.
In addition, when determining the best treatment option, we should consider the circumstances for each patient. For example, patients may be young, old, healthy, they might have a job, they might have children, or they might have other life circumstances that need to be considered. It is really important to find the right treatment for the right patient at the right time.
Some common chemotherapy regimens for MCL include R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Bendustamine (Treanda) in combination with rituximab is another common first-line treatment option. Bortezomib (Velcade) is also approved for the treatment of MCL and studies show the drug may be combined with conventional chemotherapy. For patients who have received at least one prior therapy, ibrutinib (Imbruvica) is also approved for MCL.
For patients who have relapsed or progessed after two prior therapies, one of which included bortezomib, the immunomodulatory agent lenolidomide (Revlimid) is an approved treatment option.
A lot of potential therapies exist for the treatment of MCL. Many of these therapies are acceptable treatment options and have their own advantages and disadvantages. So, it's a matter of finding the treatment that makes the most sense at that point in time for each individual patient.
Could you briefly describe stem cell transplantation?
There are two types of stem cell transplantation: 1) autologous stem cell transplantation (the patient is his or her own donor) and 2) allogeneic stem cell transplantation (the donor is another person who is genetically similar to the patient; this person is typically a brother or sister, although not always).
In the treatment of MCL, an autologous stem cell transplantation is typically performed. Within the MCL setting, an autologous stem cell transplantation is sometimes referred to as high-dose chemotherapy with stem cell rescue because, in effect, it's not a true transplant. In essence, we're taking stem cells out of an individual, giving the patient chemotherapy, and then giving the patient the stem cells back.
In the patient's body there may be lymphoma cells that are resistant to chemotherapy, and one of the ways to overcome chemotherapy resistance is to use different chemotherapy drugs. Another way of overcoming resistance to chemotherapy is to use very high doses of chemotherapy. The chemotherapy that's given with an autologous stem cell transplant does both of those. It uses different drugs, and it gives the patient a very high dose of chemotherapy. In doing so, it essentially eradicates many of the chemotherapy-resistant lymphoma cells left behind during an earlier line of therapy.
Unfortunately, it also damages other normal cells in the body. Because we use chemotherapy drugs that are toxic, primarily to white blood cells, the high-dose chemotherapy that's given with an autologous stem cell transplant also damages normal blood cells. If we were to not have stem cells stored in the freezer, that patient might lose the ability to make new blood cells, new white blood cells, new red blood cell, and new platelets. So before giving that high-dose chemotherapy, it's very important to take out those bone marrow stem cells, put them in a freezer, and then give the patient a very high dose of chemotherapy before reinfusing the stem cells. The goal of this therapy is to eradicate as many of the resistant lymphoma cells as possible, and then give back the bone marrow stem cells so the patient's body has the ability to produce new blood.
The two major advantages of having an allogeneic stem cell transplant are as follows: First, we know those donor stem cells being given to the MCL patient do not have any contamination of lymphoma in them. Whereas with autologous stem cells, the cells might theoretically have some lymphoma cells floating around, allogeneic stem cells are perfectly clean meaning there is no lymphoma there. Second, the donor cells provide a new immune system that has the potential to fight against, and potentially eradicate, the mantle cell lymphoma cells left over after chemotherapy. However, because allogeneic stem cell transplantation is associated with significant risks, it is typically reserved for scenarios where other standard options have stopped working and few options remain.
Debate exists among researchers on whether or when stem cell transplantation should be used in the treatment of MCL. Why do you think this is so?
I feel that there are really two parts to that question. One question is less debatable.
First, autologous stem cell transplantation is a procedure that requires the patient to receive high doses of chemotherapy, and not all people will be able to support a treatment that intensive. Probably less than 25 percent of people with MCL might be good candidates for intensive strategies at diagnosis. So, again, it goes back to that concept of individualizing therapy.
The second issue has to do with the respective values placed on the good and bad effects related to autologous stem cell transplantation. Although a patient might benefit from a durable remission (response to treatment lasting for a determined length of time), if that particular treatment comes along with many side effects that significantly impacts his/her quality of life or even his/her ability to tolerate the procedure, then it might not be a good option. For that person, it helps to focus on the goals of therapy. We treat any disease, any cancer in particular, with three goals in mind: 1) The first goal is to cure the disease when possible, 2) the second goal is to help people live longer, 3) and the third goal is to try to reduce lymphoma-related symptoms.
Some people feel that stem cell transplantation is likely to make a patient live longer and others feel that a long remission duration following a stem cell transplant means there are fewer lymphoma-related side effects, and everybody likes that idea.
On the other hand, autologous stem cell transplantation doesn't cure MCL. There are limited data that suggest that it may allow people to live longer, and many patients may experience significant side effects but not have a very durable remission and a longer life. So that's a very subjective sort of decision based on less than perfect evidence.
It's our job as lymphoma doctors to help patients understand the potential benefits and the potential negative side effects to all treatment options so they can select a treatment that is best for them. There's no right or wrong treatment option in many cases and it's a matter of choosing the option that makes the most sense for that person at that point in time.
What advice would you give to newly diagnosed patients with MCL?
My advice to newly diagnosed patients with MCL is to take the time to consider all treatment options in detail and find a physician and cancer center that they feel most comfortable with. They may feel more comfortable seeing a physician that has treated many people with MCL who can guide them through the complexity of their disease and thoroughly explain all of the treatment options that exist today and also all of the treatment options on the horizon.
More importantly, patients should not feel that they need to make a decision that will affect the rest of their life the very first minute they are diagnosed with MCL. Treatment decisions are complicated and rely on a lot of factors. Most people will have time to consider all of the factors and make an informed decision, and they should feel comfortable about making a more informed decision after hearing all of the options that are available to them.
What advice would you give to a relapsed/refractory patient?
In many ways, the management of relapsed (disease returns after treatment) and refractory (disease does not respond to treatment) MCL is similar to the management of newly diagnosed MCL.
Often patients have the ability to look at many different treatment options as there are already many approved treatment options and there will be new ones available in the future. Another thing that I feel is really important to emphasize is the speed with which new treatments are being developed for MCL. Many of these treatment options are likely to be far better tolerated than treatment options that were available even five years ago. I think that very often clinical trials in MCL specifically do not represent a last resort, but they represent the best treatment available at that current point in time. I would encourage anyone with previously treated MCL to research the options available for a clinical trial because there is a very good chance that those options may provide a treatment that is better than the standard or existing therapies.
How are you involved with the Lymphoma Research Foundation (LRF)? Why would you recommend a patient become involved with LRF?
The Lymphoma Research Foundation (LRF) has done more for MCL than any other organization I can think of, and they continue to do so. LRF has brought together groups of experts in the area of MCL into one room to talk about where we are with MCL, where we need to go, and how we're going to get there. It's that kind of collaboration that's been fostered by LRF that I think has the potential to move MCL research from one paradigm to the next.
LRF also serves a very important role in terms of connecting patients with information and resources specific to MCL including fact sheets, in-person educational conferences and their disease-specific website, focusonmcl.org.
How did you first become involved with LRF?
Our researchers at New York-Presbyterian Hospital/Weill Cornell Medical College have been the beneficiaries of LRF funding for MCL research to discover potential treatments and ways to eradicate lymphoma.
I had the honor of speaking at LRF's Educational Forum, which was a two-day educational meeting held in October, and I've also spoken at a LRF "Ask the Doctor" program where we discuss treatment options, clinical trials and novel therapies on this particular lymphoma subtype with patients and caregivers. These programs are a great way for patients to learn more about their particular type of lymphoma and to connect with other patients as well.