CLL: It's the Best -- and Most Confusing -- of Times

Bruce D. Cheson, MD; Susan M. O'Brien, MD


December 17, 2014

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Bruce D. Cheson, MD: This is Bruce Cheson, deputy chief of hematology and oncology, and head of hematology, at Georgetown University Hospital and Lombardi Comprehensive Cancer Center in Washington, DC. Welcome to this edition of Medscape Oncology Insights, coming to you from the 2014 annual meeting of the American Society of Hematology (ASH) in San Francisco.

Joining me is Susan O'Brien, the Ashbel Smith Professor in the Department of Leukemia at the University of Texas MD Anderson Cancer Center in Houston, and soon to be associate director of the cancer center at the University of California, Irvine.

I recently had the opportunity to review some published guidelines for the treatment of chronic lymphocytic leukemia (CLL). It struck me immediately how outdated they were, even though they were released within the past year or two. It's incredibly striking how the treatment paradigm is changing in CLL. Much of this is apparent in the abstracts at the meeting, although we did have some longer follow-up on more traditional treatments, which we will talk about first. Barbara Eichhorst[1] updated results from the CLL10 trial, the head-to-head comparison of fludarabine, cyclophosphamide, and rituximab (FCR) with rituximab/bendamustine (BR). What's your spin on those data?

CLL10 Trial Update: FCR vs BR

Susan M. O'Brien, MD: This is an interesting randomized trial in the following sense: Everybody came out of this trial happy, which is not very common. When you compare A with B, there are always people who think A is better, but they can't prove it, and people who think they prefer B. Then if A wins, everybody who really liked A is very happy, and if B loses, anybody who liked B tells you why it was such a poorly designed randomized trial.

This one made everybody happy because people said FCR is better. It's going to produce better outcomes than BR. And other people said, "But BR is easier to give, and that's why I like to give it."

Dr Cheson: Tastes great, less filling.

Dr O'Brien: And both of those turned out to be correct. The FCR was a better regimen in terms of complete response (CR) rate and minimal residual disease (MRD) negativity, which may be very important with further follow-up, as well as progression-free survival (PFS). But BR was less myelosuppressive and caused fewer infections.

Dr Cheson: And the survival was the same.

Dr O'Brien: But the follow-up is short. It's a frontline trial.

Dr Cheson: There were other issues. Obviously, you are the FCR person and I'm the BR person at this table. Serious infections were more common. And it was mostly in the younger patients, where FCR demonstrated a possible advantage. There was also, albeit with small numbers and short follow-up, concern for increased secondary malignancies. Over time, do you expect that there will be a greater difference, given fludarabine and cyclophosphamide?

Dr O'Brien: Our experience is that there is an incidence of secondary acute myeloid leukemia or MDS after FCR, but that it's a low percentage. What is interesting is that I have never seen data published for BR. Bendamustine is a very potent alkylating agent but doesn't have the purine analog with it, so one could hypothesize that the incidence would be lower because it only has one alkylating agent, depending on how important you think the alkylating agent is in the underlying pathogenesis. There are no data for BR, so this trial will show us some important data with longer follow-up.

Dr Cheson: That has been one of the biggest criticisms of bendamustine development: the lack of long-term, systematic follow-up for infections, secondary malignancies, etc. We will have 5- and hopefully 10-year follow-up on this study. But let me throw this one at you: Do we care?

Dr O'Brien: That's a good question. Historically, we cared for a couple of reasons. One is, what happened if patients relapsed? We had to give them chemotherapy again. We also care because we have data that Bill Wierda[2] presented, showing that with FCR in the mutated population, we have what appears to be a plateau on the PFS curve at 10 to 14 years.

Dr Cheson: Young, fit, and mutated.

Dr O'Brien: Now, are they cured? I don't know. If they are in remission 14 years after having 6 months of chemo, that's probably pretty good. But obviously now, we have the novel agents. Do they need to become MRD-negative when, if the patient relapses, you have a much better therapy to offer them?

That is a hard question to answer. I would be very cautious in the group who were on this plateau of the curve. They are probably in the minority. I don't think they are as small as you are implying, Bruce, but they are the minority. Do we need to give all six cycles? Can we just debulk the patient and then switch them over?

Dr Cheson: You have data which suggests you don't, right?

Dr O'Brien: If they are MRD-negative after three cycles, but that is only 20%-25% of patients who receive FCR. So it's a difficult question to answer. Historically, if all you had to give patients was chemotherapy, then yes-the longer the remission, the better, because you didn't have to give chemotherapy again. With each round of chemo in CLL, like low-grade lymphoma, you start to have less bang for your buck every time you have to come back to it.

Best Frontline Agent?

Dr Cheson: If the new drugs were available for frontline therapy and the standard non-17p patient walked in the door-a 50- to 55-year-old patient with CLL-and you could give him ibrutinib, idelalisib-rituximab, or FCR or BR, what would you do?

Dr O'Brien: In the subset we are talking about, it's a hard question. Let's take older/unfit patients first, however you want to define that.

Dr Cheson: Be careful how you define it.

Dr O'Brien: I would give those patients a novel agent because I don't care that much in that population-in an 80-year-old-if they're going to have an MRD-negative complete response. It is much less relevant, and toxicity is much more important. If I could do it today, in an older patient, I would go straight to a small molecule.

What is another group I might say that about? Unmutated. Now, the unmutated patient gets several years of remission with FCR. If you look at the shape of the curve, there is no suggestion of a plateau, and they all relapse. I would be willing to do it today to pretty much everyone except the group who are mutated, and in particular, if they have trisomy 12s, which is very favorable with FCR. In that case, I would be more wary, because if you look at the frontline-for example, ibrutinib data or idelalisib-rituximab data-the longest follow-up, which is for ibrutinib, is 3 years. We just don't have those long-term data.

The Mutated Patient

Dr Cheson: Yes, but the problem patients remain those with 17p deletion. Data were presented at this meeting on both ibrutinib from the RESONATE trial[3] and idelalisib-rituximab,[4] showing some promising results in this population. And what do you think about those data?

Dr O'Brien: The front-line data with these regimens I think look very good, but I will make the same comment. We don't have 5-year or 10-year follow-up.

The other interesting question is that we talk about the B-cell receptor inhibitors not resulting in CRs, which is clearly true in the relapsed/refractory patients. That would be a rare event. I don't think we know what the CR rate is going to be when these agents are used up front, because there are patients who aren't relapsing and are staying on the drugs for 2 or 3 years and achieving CRs. It takes quite a while, but we are beginning to see CRs with frontline use, although not so much in the relapsed setting.

Dr Cheson: Are they MRD-negative or just CRs?

Dr O'Brien: I have only ever seen one MRD-negative patient, but maybe that will take even longer. The way we think about this is that partial response with lymphocytosis is predominant with ibrutinib, but not as much with idelalisib because you give the rituximab. It takes a while to achieve a partial response, and then it takes a while to achieve a CR. Obviously, in a relapsed population, the competing risk is losing the response, and we see the PFS going down. With a lot longer follow-up, I don't think the CR rate is likely to go up a lot in that population.

If you look at the patients in frontline, very few of them are actually progressing. They are staying on the drug and they could potentially improve their response. It will be interesting to see with longer follow-up; that would change my impression a lot if I knew I was achieving CRs with the drug.


Dr Cheson: We have those two drugs on the market and we have ABT-199 banging at the door. Let's say they are all available; which one do you pick?

Dr O'Brien: I'm not telling you that.

Dr Cheson: The worst question-okay, then don't. ABT-199 is being presented here,[5] and that seems to be pretty good. Unlike the other two "i" drugs we were talking about, it does achieve MRD-negative CRs in about one fourth of patients. Is MRD negativity with a kinase inhibitor the same as MRD negativity with chemotherapy?

Dr O'Brien: My reply would be "probably."

Dr Cheson: Would this drug be better before those, or would it be better to try and fix them if they don't work?

Dr O'Brien: One thing that we don't have much data on for any of these drugs-there are a little data, but not much-is what happens if a patient fails one drug, and how does that affect the likelihood of responding to another drug. That will come out with time, but we don't have that information right now.

The MRD-negative CR is a relevant endpoint, but it's a minority. Certainly, if there was something that could predict-and I haven't seen this analysis done-but if they could look at the people who become MRD-negative and sort out what subset that is, then you might want to focus on them. Would I just want to give the drug to everybody first, which is what you're really asking me, because of that MRD-negative subset? I don't know because when the outcomes of this drug were presented at the European Hematology Association meeting this past year,[6] the median PFS curve in the patients who got to the target dose of 400 mg was slightly above 50% at a year and a half, so you get the feeling that it's going to be about a year and a half, which might be shorter than some of the other drugs. So maybe I wouldn't want to give it to everybody first. This is with the caveat that we are comparing different trials.

Dr Cheson: There is a trial looking at ABT-199 in patients who have failed one of the "i" drugs, so that will be an important study. I think that there is a lot of work ahead of us. One thing we are lacking, as you alluded to, is biomarkers to tell us who is going to respond to which drug and in which order and what to do about it. It's a double-edged sword. It's the best of times and the most confusing of times. We have a lot of work, but it's great for patients that we have all of these drugs and new ones coming down the pike all the time.

I would like to thank Susan for joining us here at Medscape Oncology. And thank you to the audience for joining us for this edition of Medscape Oncology Insights. This is Bruce Cheson, reporting from San Francisco, ASH 2014.


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