CLL: Factors for Upfront Therapy


Thomas J. Kipps, MD, PhD: In terms of defining treatment options, chemoimmunotherapy is a useful treatment. It can induce a high rate of remission in the right type of patients. I think with the advent of newer therapies, we shouldn’t dispense with the idea of using chemoimmunotherapy. For example, in some patients chemoimmunotherapy can induce a very deep remission that may last years and years—over a decade. And are some of these patients cured? We don’t know.

The factors that are associated with a favorable outcome to chemoimmunotherapy-based regimen are really the absence of deletions in chromosome 17. So, if you have leukemia cells where you find deletions in chromosome 17, it’s likely—not invariably, but likely—that you’ll have a mutation in the gene that encodes p53. Therefore, the ability to respond to chemotherapy is not as great. So, the cells are relatively resistant to treatment but your bone marrow cells are just as sensitive as everyone else’s, and so you just have the toxicity without the benefit of effective therapy.

The other factor that weighs in on this is the mutation status of the immunoglobulin genes. If you have leukemia cells that express unmutated antibody genes, there’s a shorter time between diagnosis and requiring therapy, and there also appears to be a shorter time from successful therapy to relapse after therapy than with patients who have mutated antibody genes. And so, if we’re trying to get a homerun with chemoimmunotherapy and have a long-lasting remission after therapy, it’s more likely to occur in patients who have leukemic cells that express mutated antibody genes that lack the deletion in chromosome 17.

The FCR chemoimmunotherapy is an intensive regimen that involves 3 drugs: fludarabine, cyclophosphamide, and rituximab. The BR regimen has only 2 drugs: bendamustine and rituximab. By far, the most active agent in either regimen is the drug rituximab. This is a monoclonal antibody that targets the protein CD20 on the leukemia cell. So, this is common to both regimens, and it’s been shown that with the use of rituximab in chemoimmunotherapy as opposed to just chemotherapy, with either fludarabine and cyclophosphamide by themselves or bendamustine by itself, that you have a much more favorable response and a much longer progression-free survival. So, both regimens share that.

It used to be said, and some people still argue, that FCR chemoimmunotherapy is a stronger regimen, and therefore may be more effective in inducing very deep remissions that may be long-lasting compared to the BR regimen. And I certainly share that opinion. However, the Germans did a study—the German CLL study group—where they compared patients receiving FCR therapy versus BR therapy. I think the idea was to find out what regimen was better.

Unfortunately, for some reason, the 2 groups of patients were not the same. In other words, the patients who had BR as a regimen were significantly older, and a significantly higher percentage of those patients had leukemia cells that expressed unmutated antibody genes. So, if I were to give the 2 groups of patients the identical therapy, I would predict that the patients who had the BR regimen would actually have a shorter progression-free survival.

However, when they did the analysis, it was very difficult to distinguish the progression-free survival, at least at this point, between FCR treated patients and BR treated patients. I think over time we’re going to see the lines diverge, and we’re going to see a benefit in patients who achieved a complete remission with FCR chemoimmunotherapy versus the BR treated group.

Now, because of the fact that the 2 groups were not equal, I don’t think we could say it’s the final word in terms of defining the benefit of FCR versus BR. Know this, that BR is a simpler regimen. It’s also a regimen that can be very easily maintained and observed for toxicities. There’s probably a lower incidence of very late complications, such as myelodysplasia, when you take out the drug fludarabine, which can sometimes result in acute myeloid leukemia in patients several years down the road. And also, I think patients who’ve had FCR chemoimmunotherapy typically have had a higher incidence of infections and problems with marrow recovery after therapy. I think the jury’s still out for me, in terms of the superiority of one regimen versus the other. I know this is controversial. Some people argue FCR is the be-all and end-all, but I’m not sure.

I think what’s important to note is that there’s a new kid on the block. Namely, new antibodies—a second generation anti-CD20, ofatumumab, and more recently, obinutuzumab, or Gazyva. I’ve had some patients describe obinutuzumab as rituximab with an attitude. It really is. It’s been engineered to have a greater activity against leukemia cells. And so, patients are getting a deeper remission in regimens that combine chemotherapy with obinutuzumab versus rituximab.

We’ve done studies here, and we published in the Blood Journal a few years ago, where we had patients treated with bendamustine and obinutuzumab—this drug called Gazyva. And we had response rates on par with what might be achieved with FCR, it was very well tolerated, and we had many patients who achieved disease remission. So, we’re dealing with a changing playing field. As we change with regard to the types of other agents that we can combine with chemotherapy, we may change the paradigm somewhat, making it difficult to know for sure whether or not drugs such as FCR versus BR have superiority.

Transcript Edited for Clarity

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