Fred D. Lublin, MD: You bring up one of the issues now. We’ve seen this now with cladribine. We haven’t with alemtuzumab, and we haven’t with the autologous stem cell transplantation in the bone marrow transplant. You have a period where you’re not doing anything therapeutically, where people have some degree of protection. None of them are a cure. There is different cost effectiveness. One of the things I’m struggling with is, when do you restart the therapy? If you hope that you’re going to see something on the MRI [magnetic resonance imaging] as the first sign, and that may be OK because MRI is very sensitive, but if the next event is a relapse and that’s what you make the decision off of, well, 50% of relapses leave some residual disease. And so, you probably have waited too long.
How are we going to make that decision of how long? I mean, here you have data for 2 years. It’s group data, not individual data. We have the same thing with alemtuzumab. There are some people who fail all along, and if you look at the well-done autologous stem cell transplants, they all have a failure rate out through 2 years and moving onward, and some more than others. How are we going to be able to protect those individuals?
Suhayl S. Dhib-Jalbut, MD: Theoretically, you want to look at the target of the drug and see if the target is adequately suppressed or modified. For example, if you were using a B-cell depleting agent, you would hope that B-cell counts, CD19, for example, would be a good indicator for when to administer the next dose. But, as you pointed out, patients may have a relapse before then, while their CD19 are still undetectable. What does this tell us? It probably tells us that it’s working through additional mechanisms, and maybe that’s not the absolute biomarker for timing the next dose of the drug. One could say the same thing for alemtuzumab. You might have suppression of a lot of the target cells, the CD52 cells, yet the patient might have a relapse. Well, what could be happening is that maybe those patients have not yet developed regulatory T cells, which we know, in the context of alemtuzumab, appear later in the disease during a treatment course. So the point I’m trying to make is that we try to use the target of the drug as an indicator for dosing, but it is not always the case that they’re predictive. But they do tell us that these drugs, while we think they work through 1 mechanism, probably involve several mechanisms, some of which we don’t know.
Fred D. Lublin, MD: And what do you do with people when they have no T cells and are having an attack, but alone, just not having B cells? I think that’s still an open question, as to what to do then.
Thomas P. Leist, MD, PhD: We also need to keep in mind that what we measure peripherally in B cells or T cells is not necessarily completely reflective of what’s present within the tissue. And so, while the peripheral component of the lymphocytes is certainly something that we traditionally measure and look at, it may not necessarily fully inform us, with these treatments, how it is actually represented in the target or how it regulates the disease process.
Fred D. Lublin, MD: There’s some rather old data in irradiated mice that show you can get attack of the nervous system with very few T cells and still produce damage.