Dr. Armitage: For ALK-negative anaplastic large cell lymphoma, brentuximab vedotin is the best thing we have to deal with patients with recurrent disease, and who knows where it will end up in primary therapy. But if the patient is ALK-positive, there is a potential for crizotinib (Xalkori) to make a big difference, even though it has been developed for lung cancer. Have you had any experience with crizotinib?

 Dr. Horwitz: No. We have not used crizotinib. ALK-positive disease is often cured, and our bias is that patients fare better with second-line therapy and stem cell transplant, but I do not think we really know. Our sense is that ALK-positive disease is more chemosensitive, so we have not used the drug. There have been a couple of anecdotes and small series presented at meetings, about a couple of adult patients who responded. And there was a small group of patients in a pediatric ALK-expressing tumor study presented at ASCO [2012 Annual Meeting]. Six out of seven or eight patients responded, so it looks very promising. Those are rare patients, but I think crizotinib is something that could be used here. I do not think we really know the durability nor how to incorporate that into curative therapy yet, but the agent probably is very active.

 Dr. Armitage: Dr. Horwitz, what is your sense of the durability of responses induced by brentuximab?

 Dr. Horwitz: It is hard to say. A number of the patients in the phase II study went on to transplant. I think a lot of my bias comes from the fact that if the patient has relapsed after combination chemotherapy, the likelihood that one drug will be curative is probably low. So if a curative approach is available, then we often take that approach.

Among the patients who had a complete response and did not undergo transplant, a number of those still have ongoing remissions, some of them have been retreated or are on continuous therapy, and some of them have been off therapy. The numbers get pretty small, but there is probably a subset of patients who have pretty good durability.

For the patients who did not have a complete response—so their durability is probably quite short—with the data we have now, my advice is that it probably makes sense to move on to something else.

 Dr. Armitage: The big question right now is, can we cure these patients eventually with brentuximab alone? Some patients have been on treatment for a year or longer. Alternatively, should they undergo allogeneic transplantation or autologous transplantation if they had not had an autologous transplantation previously? We don’t have the answers to these questions right now, but these are the issues we have to address in the future.

 Dr. Connors: The natural experiment is playing out, because there will be patients for whom, either through choice or lack of available donors, the last treatment they received is brentuximab. If, in a year or two or more, we see that they are not relapsing, then we have our proof in hand. But it would probably be a surprise to all of us if we suddenly cured such an otherwise treatment-resistant disease with a single agent. So we better remain open-minded about it.

 Dr. Armitage: Now we are talking about odd situations, but there are some people with cutaneous anaplastic large cell lymphoma who keep relapsing even though you can treat each one with radiotherapy or something else easily. There are people with lymphomatoid papulosis in whom treatment is challenging because the disease is continuously active. Have you treated any of those people with brentuximab, since they both express CD30?

 Dr. Horwitz: We have, as part of a study. We think about primary cutaneous anaplastic large cell lymphoma as indolent, and lymphomatoid papulosis was spontaneously regressing, but people can get really symptomatic disease. We have treated two people with lymphomatoid papulosis using brentuximab vedotin as part of a study. Both responded, though the durability was short. We have probably treated three people with primary cutaneous anaplastic large cell lymphoma who then subsequently developed nodal disease. So, treating patients in that setting, two had good responses, although with relapses in the skin. My sense right now is that it is too early to say, but it probably is not curative in those chronically relapsing populations, at least not off therapy.

 Dr. Armitage: Dr. Connors, Dr. Engert, do you have anything to add about these challenging situations?

 Dr. Engert: One open question is, how do patients fare, for example, those with Hodgkin lymphoma, when they have not had a transplant before?  Because these were the patients who were not included in the pivotal study, and there were discussions in the United States and also in Europe as to whether the drug should be used in these individuals.

We collected 16 of these patients who were either too old or too sick for transplant, and we observed quite an encouraging response rate, allowing 6 of these 16 to go to autotransplant and stay in remission for at least until now. So that is a very interesting area, as is the issue of elderly patients who cannot receive transplant at all if they relapse.

 Dr. Connors: Conceptually, I think a transplant-­ineligible patient is in just as much trouble when his disease relapses after primary therapy as he would be when relapsing after a transplant. There are not a lot of reliably curative options on the table, so I think that exploring the use of brentuximab in that population is going to be very rewarding.

 Dr. Armitage: Dr. Horwitz, do you have a last word?

Dr. Horwitz: One of the things we are learning as we are looking at this drug in CD30-expressing T-cell lymphoma is that there is a lot of variability in terms of expression, and in terms of different compartments being positive and negative. For example, we see a lot of negativity in bone marrow.

We have a very exciting drug that hits this target, and there is still a lot to learn about how we are interpreting that target, how much expression is needed, and how we look for that. ■