What You Need to Know About Transformed Lymphomas
Lymphoma Research Foundation Lymphoma Today newsletter, Summer 2007
Q & A with Andrew Zelenetz, M.D., Ph.D.
By Jo Cavallo

Although indolent B-cell lymphomas, such as follicular lymphoma, are most commonly associated with transforming to aggressive disease, slow-growing T-cell lymphomas can also progress to aggressive disease. We asked Andrew D. Zelenetz, M.D., Ph.D., Chief, Lymphoma Service, Memorial Sloan-Kettering Cancer Center in New York City to explain why indolent lymphomas become aggressive and how to tell if your disease is transforming.

LRF: What are transformed lymphomas?

Dr. Zelenetz: It is the transformation of an indolent slow-growing lymphoma both clinically and under the microscope to an aggressive disease both under the microscope and clinically. I am making these distinctions because there are some patients who have indolent follicular lymphoma and then they end up with quite aggressive disease but their biopsy still looks like follicular lymphoma. That is not a transformation, that is a more aggressive behavior of a follicular lymphoma and it might be that they are genetically related. That is a true transformation and a transformation to more aggressive-type of behavior might, in fact, represent similar molecular events. But when we talk about transformed lymphoma we mean the switch from a slow-growing indolent disease with an indolent clinical history to a more aggressive appearance under the microscope and a more aggressive clinical history.
It is important to identify transformation because it represents a change in the biology of the disease and in the patient’s clinical course. The patient is going to have more rapidly progressive disease and that demands more aggressive treatment. And what that treatment is going to be depends on what disease is transforming and when it transformed in the course of the disease because some transformations have a very poor prognosis.
LRF:  Does transformation mean having a new type of lymphoma or a second lymphoma?

Dr. Zelenetz:  Now this is an interesting and somewhat controversial question. The tumor cells fundamentally change and go from small cell to large cell. A number of different molecular investigations have looked at the relationship between the indolent slow-growing disease and the aggressive transformed disease. The classic situation in which this happens is when follicular lymphoma goes to diffuse large B–cell lymphoma. In that setting, it is virtually always one clone getting additional mutations. It’s the same clone of cells but it has new genetic alterations that result in an aggressive lymphoma. In some cases when chronic lymphocytic leukemia (CLL) transforms to aggressive disease, known as Richter’s Syndrome, most of the time you can show it is the same clone that’s evolved just like in follicular lymphoma. However, there are some cases where it’s very hard to identify the relationship between the new lymphoma and the second lymphoma and it looks as if it really is a second lymphoma, not an evolution of the first. The answer is that in most cases it is an evolution of the same clone of cells that acquires additional genetic abnormalities, which gives it a growth advantage and becomes much more aggressive. But in a few instances, it appears to be the emergence of a second lymphoma that is unrelated to the first, but that is less common.

LRF: What types of B–cell and T–cell lymphomas are at risk of transformation?

Dr. Zelenetz:  Any disease that is indolent and slow growing could potentially become transformed and aggressive. The classic example is follicular lymphoma going to diffuse large B-cell lymphoma, but we see CLL going to large cell lymphoma too. We also see some cases of slow-growing mantle cell lymphoma going to blastic mantle cell lymphoma. But we even see transformation in the T–cell lymphomas. Multiple recurrent disease of the skin can sometimes develop into an aggressive large-cell lymphoma, so you can see transformation of even cutaneous T–cell lymphoma to aggressive lymphoma. And we also see it in marginal zone lymphomas where they can go from a slow-growing disease to aggressive diffuse large B–cell lymphoma.
LRF: Does the risk of transformation increase with time?

Dr. Zelenetz:  The risk per patient per year looks to be pretty steady. If you look at what we call a cumulative risk curve, it’s linear. For example, in follicular lymphoma the estimated risk of transformation varies from 1½ percent to 3 percent per year. At 3 percent per year, half the patients will have transformed within 15 years. So the risk increases with time simply because there’s more time. Transformation in chronic T–cell cutaneous lymphoma is also low, around 1 percent or less per year, but it does happen.
LRF: How is a diagnosis of transformation determined?

Dr. Zelenetz: If there is a suspicious area that is growing rapidly or if there is an area on a PET scan that’s particularly hot compared to the other areas on the PET scan, these are hints of transformation and we recommend a biopsy.
LRF: What treatments are available for transformed lymphomas?

Dr. Zelenetz: The treatments are really tied to the clinical circumstances. If a patient has had minimal prior therapy and is now going to be treated with an aggressive course of combination chemotherapy, he is likely to have a good remission. A patient who has had a course of chemotherapy and the disease recurred and he got another course of chemotherapy and then the patient gets a transformation, he will need very aggressive therapy, maybe in the form of a bone marrow transplant. So the therapy is dictated by the timing, extent and prior treatment history of the patient.
LRF: What’s new in research and in clinical studies for transformed lymphomas?

Dr. Zelenetz: Transformed lymphomas can represent a challenge in clinical trials. I think to do a proper trial requires a biopsy because many of these patients don’t get biopsied, they’re just getting treated. One of the classes of drugs that appear to be active for transformed lymphoma is radioimmunotherapy. We had described some activity of suberoylanilide hydroxamic acid (SAHA) in the treatment of a transformed lymphoma, but that was a very preliminary study and it needs to be validated in larger patient populations.
LRF: Do you have suggestions for people with transformed lymphomas or those that might be concerned about it?

Dr. Zelenetz: A patient with a slow-growing indolent type of lymphoma that notices a stark change with development of new night sweats or fevers or the appearance of rapidly growing lymph nodes in one or more areas that seems quite different than the growth pattern from before, are all indications that the patient needs to be urgently seen and evaluated by a lymphoma specialist for the possibility of transformation. A full evaluation should include a biopsy.