Combination Treatments in CLL

Susan M. O’Brien, MD: I think that the single agents, in terms of the targeted therapies, have proven to be very effective in CLL. But, I also think that there’s room for improvement. For example, there’s very low CR rates, so we’re not necessarily getting rid of the disease. One really nice endpoint would be if we could have high CR rates and the potential for actually stopping therapy, rather than continuing therapy, for years and years. We are beginning to see trials now combining the novel agents, so perhaps one B-cell receptor inhibitor with another one or a B-cell receptor inhibitor with a BCL-2 inhibitor, plus or minus an antibody. And I think there’s a lot of excitement that, given how active each of the single agents are, we may see, when we combine them, very high CR rates. And that would give us the potential to stop therapy in patients rather than dosing indefinitely.

It’s clear that the targeted agents which have been approved for relapse have become the treatment of choice in the relapsed setting. Very recently, one of these agents, namely ibrutinib, received a frontline approval. And although the trial that led to the positive benefits versus chlorambucil was restricted to older patients, in fact, the label that they received from the FDA is just a very broad label which is not age-restricted. What that means is that, theoretically, any patient of any age now who needs therapy, could receive ibrutinib. The important question is, should they all receive ibrutinib? That is where it becomes not that clear.

For example, I think for the elderly patients or the ones with a lot of comorbidities, where it’s very hard to give chemotherapy, it’s very clear that everyone would give those patients ibrutinib. But, what about the younger, fit patients? How would I decide where they should get chemotherapy, immunotherapy, or ibrutinib? Well, there’s been three recent publications looking at the long-term outcomes of frontline therapy of CLL with FCR (fludarabine, cyclophosphamide, rituximab): one from MD Anderson, one from the Germans, and one from the Italians. The MD Anderson one has the longest data, but all three of those publications are very consistent in showing a very prolonged progression-free survival, and, importantly, a suggestion of a plateau on the curve for the patients with a mutated IgVH gene.

What I would look at is the mutation status. Because, in fact, if you look at the MD Anderson data with the long-term follow-up, about 60% of the patients with a mutated IgVH gene are still in remission 12 to 16 years later. And there’s the distinct possibility with that plateau on the curve that they actually may be cured. But, even if they’re not cured, it’s hard to argue with 6 months of therapy producing a 15-year-plus remission. So, in that group, I think it’s a much more complicated discussion with the patient and decision making as to whether you want to forego that potential long-term benefit for an easier therapy to give upfront, which would be ibrutinib. And those are the patients where it’s not 100% clear that we should be throwing out chemotherapy, and where we have to have much lengthier discussions with the patients.

I think ibrutinib clearly has a role in relapse, and it’s probably the agent of choice at this point in time. But, obviously now, if we’re going to have frontline treatment of ibrutinib, then some of the relapse options would be different if the patient has progressed on ibrutinib. The other option, as I mentioned, is that chemotherapy may still play a role in some patients in the frontline setting who have a mutated IgVH gene, and may benefit from very long progression-free survival. So, I would say in the relapsed setting, it’s probably my treatment of choice. And in the frontline setting, it would be my treatment of choice for older patients, and perhaps patients with an unmutated IgVH gene, but not necessarily those with a mutated IgVH gene.