T-Cell Lymphomas: Moving Forward, Improving Outcomes

An Expert Interview With Julie M. Vose, MD

Shira Berman; Julie M. Vose, MD

Disclosures

January 23, 2013

Editor's Note:
T-cell lymphomas are a heterogeneous group of uncommon subtypes of non-Hodgkin lymphoma that typically carry a poor prognosis.[1] The publication in 2008 of the updated WHO Classification of Haematopoietic and Lymphoid Diseases[2] was a first step toward developing a better understanding of how to distinguish among the many subtypes, and the International Peripheral T-Cell Lymphoma (PTCL) Project provided a worldwide collaborative view of how PTCL behaves in the clinic.[3] Ultimately, these efforts succeeded even more in shedding light on how little we understand about the biology and natural history of these diseases.

In an interview with Medscape, Julie M. Vose, MD, Professor of Internal Medicine in the Division of Hematology & Oncology at the University of Nebraska Medical Center in Omaha, discussed how research into the pathogenesis of T-cell lymphomas, and particularly PTCL, is providing new insights into strategies for improving diagnosis and management of these diseases.

Medscape: Traditionally, what have been the challenges in diagnosis and management of PTCL, and how has this led to the current research efforts under way?

Dr. Vose: There are a number of different histologies for PTCL, and as we understand more and more about the clinical diseases and about the pathology and genetic changes in this disease, we're discovering that there are even more and more subtypes of PTCL. Although they often have very different clinical outcomes, the majority have poor clinical outcomes with standard therapy. Most of the research now is focused on understanding these different types of PTCL and understanding the genetic changes underlying these diseases. The next step would be to identify specific genetic changes that might be targeted with therapy.

Types Common in Asia Are Uncommon in Europe

Medscape: The International PTCL Project noted that different types of PTCL were more common or less common across geographic regions.[3] How might these findings be helpful to physicians in diagnosing, classifying, and, ultimately, treating patients with these diseases?

Dr. Vose: We knew that the geographic distribution of a number of different types of T-cell lymphomas was widely variable throughout the world, but the study brought these data forward even more.

There were a few unexpected findings. For example, angioimmunoblastic T-cell lymphoma (AITL) turned out to be much more common in Europe as compared with other parts of the world. On the other hand, we knew that NK/T-cell lymphomas and AITL were much more common in Asian countries, and the studies bore that out as well. Differences in distribution of anaplastic large cell lymphoma (ALCL) were also seen in Europe vs the United States. The prevalence similarities in some areas may point to genetic changes consistent with populations in the United States that have a northern European background and led to ongoing research that is looking at genetic predisposition to different types of lymphomas.

Because we don't really know the contribution of ethnicity vs environmental factors, it is difficult to say whether an immigrant population would be more likely to develop PTCL subtypes consistent with their background. Usually, the first generation still has the same genetic background as those in the country of origin, so you would often see the same types of lymphomas. Past the first generation, it seems to level off a bit, but it does not change enough to be like the other ethnicities in that area. This tells us that there must be some combination of genetics and environment affecting development of different subtypes.

Regardless of whether the patient's ethnicity can help point to the diagnosis, as a general statement, the more clinical information you can give the pathologist, the better they are able to distinguish some of these really rare subtypes.

Prognosis Is Often Poor

Medscape: What do we know about prognostic features for different subtypes that might affect management strategies?

Dr. Vose: In general, most patients with T-cell lymphomas have many poor prognostic features, and a much higher percentage will fit into the poor prognostic group as compared with those who have B-cell lymphomas. So although the standard prognostic features that we think of in patients with B-cell lymphomas apply, they aren't as distinguishing a characteristic because the majority of patients are all in the poor-prognosis group, whereas in the B-cell lymphomas it's more of a spread.

The one type that's a little bit different is ALCL, which has a somewhat better prognosis. We've always known that patients with ALK-positive ALCL do better than those with ALK-negative ALCL, but it seems that those with ALK-negative ALCL are intermediate in outcome compared with other PTCLs.[4] Looking into that further, we found that in patients who were younger, specifically under age 40 years, it didn't really matter whether they were ALK-positive or ALK-negative because both groups had a good outcome. In patients over age 40 years, those who were ALK-positive still did pretty well, but those who were ALK-negative were like the rest of the patients with T-cell lymphomas and didn't do very well. This is an important distinction because we don't want to bundle in those who might fare better with the patients with other T-cell lymphomas and treat them all the same.

Medscape: Research in B-cell lymphomas has focused on therapies that target the underlying mechanisms of disease, but practitioners still use standard cytotoxic chemotherapies for certain B-cell lymphomas because they often show good outcomes. How is that different in T-cell lymphomas?

Dr. Vose: Unfortunately, those same types of chemotherapies don't work very well for T-cell lymphomas, so there's a bigger push to try to find other types of therapies that are more targeted to specific pathways that we know are abnormal in T-cell lymphomas. They're either being used as single agents for patients with relapsed disease or perhaps in combination with some of the standard agents for upfront disease.

Pathways to Better Outcomes

Medscape: What do you consider to be some of the successes in terms of identifying pathways that we think might be critical and/or unique to these groups of cancers?

Dr. Vose: The HDAC pathway appears to be important in T-cell lymphomas, and the HDAC inhibitors vorinostat and romidepsin are approved by the US Food and Drug Administration (FDA) for use in cutaneous T-cell lymphomas.[5,6] They probably won't be home runs by themselves, and we're likely going to have to combine them with other agents that target other pathways. I expect that we'll require multiple agents together to block all of the different pathways, and that's the way that most of the research is going now. So, for example, in addition to the HDAC inhibitors, researchers are looking at aurora kinase inhibitors[7] and some of the PI3K/AKT inhibitors[8] -- those all work in the same pathway but at different junctures, so they may be able to be combined in some way.

Then, of course, we have brentuximab vedotin for ALCL, where targeting CD30 has proven to be very efficacious.[9] Unfortunately, of the cell surface receptors studied, CD30 is the only one that has been shown to be a useful target in T-cell lymphomas. Others have not really worked out so far.

Many of the trials right now are using these agents in combination with cytotoxic chemotherapies, or, in some cases, as a maintenance type of treatment after chemotherapy.

With the antifolates, we've always known that methotrexate has some activity in T-cell lymphomas, and pralatrexate, which is FDA-approved for PTCL, is a little bit more potent than methotrexate, with about a 30% response rate.[10] That particular agent is a little more difficult to combine because of some of the side effects, but there are some combination studies going on.

Medscape: The number of patients with any one particular subtype of PTCL is fairly small. How do you account for this in clinical trials in trying to figure out whether there are specific subtypes in which a drug might work better?

Need for Greater Enrollment in Trials

Dr. Vose: Usually the first trials are open to patients with all different PTCL subtypes, and then maybe, if there are 1 or 2 that seem to stand out, we might do further trials just in those sub-subtypes. But most of the trials are all-comers because there aren't enough patients.

In fact, our biggest problem moving forward is that we don't have enough patients to put on trials and therefore don't have enough specimens to study. We need clinicians to encourage patients to go on trials and to donate specimens. And we also need researchers to work together. Right now, there are so many different trials that you can't get enough patients in any one trial. We need for the physicians to work together more effectively.

Medscape: Is there a benefit to referring a patient with T-cell lymphoma to a specialty center?

Dr. Vose: Yes. Guidelines, such as those from the National Comprehensive Cancer Network,[11] recommend CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone] or other chemotherapy regimens that are not very helpful. With these really rare types of cancers, I think clinicians would be doing their patients a real disservice not trying to find better options for them.

Medscape: Finally, what are your general thoughts on T-cell lymphomas, looking back at where we started and where we're now headed?

Dr. Vose: What we've understood over the past few years is that there are so many different subtypes of T-cell lymphomas and that it is very important to try to recognize these different subtypes so we can potentially treat them differently. But these cancers are so uncommon, we have to be ready to cooperate on clinical trials or we're not going to learn anything. And, actually, that's true for all rare types of lymphoma and every other rare disease.

processing....