ASH 2016: An Interview with Dr. John Pagel on Maintenance Therapy in CLL

At ASH 2016 in San Diego, much of the chronic lymphocytic leukemia (CLL) buzz was about the new data on the durability of the responses to ibrutinib and on some powerful new therapeutic combinations.

However, an older drug, lenalidomide or Revlimid, that is usually used to treat multiple myeloma, was found to provide a significant benefit as maintenance therapy in CLL for progression-free survival (PFS).

How lenalidomide works is not completely understood, but it seems to modulate our immune system in a way that suppresses our cancer.

Dr. John Pagel of Swedish Hospital in Seattle explains the potential importance of this new finding.

Take Away Points

• Maintenance therapy, while commonly used in other lymphomas to delay the time it takes for the cancer to return after being successfully treated, is not used much in CLL
• This German trial focused on maintenance therapy in high-risk patients where the risk of the disease coming back quickly was higher, and if it did, it would be harder to treat.
• Lenalidomide is an oral medicine with potentially serious side effects, but was well tolerated in this study.
• There was more than an 80% reduction in disease progression (PFS) during the study.

The link to the raw data and the actual ASH abstract is here: Lenalidomide Maintenance after Front Line Therapy Substantially Prolongs Progression Free Survival in High Risk CLL: Interim Results of a Phase 3 Study (CLL M1 study of the German CLL Study Group).  The details are impressive.

Another study of lenalidomide maintenance in a different group of patient also showed a similar result with a significant improvement in PFS from 9.2 to 33.9 months, but no change in overall survival (OS). The abstract can be found here: Results of the Phase 3 Study of Lenalidomide Versus Placebo As Maintenance Therapy Following Second- Line Treatment for Patients with Chronic Lymphocytic Leukemia (the CONTINUUM Trial)

As long as CLL (chronic lymphocytic leukemia) remains largely incurable, looking at well tolerated ways to prolong the time one is free of disease and feeling well is a  worthy area of research.

Dr. Pagel goes into much more detail in our interview. Please enjoy reading or viewing the video interview below.

Dr. Brian Koffman: Hi, Dr. Brian Koffman. I’m a family doctor and a CLL patient and I’m the founder and the volunteer Medical Director of the CLL Society. I’m here in the last hours of the American Society of Hematology Meeting 2016 in beautiful San Diego.

Dr. John Pagel: Yeah, hello, great to be with you. I’m John Pagel. I’m a CLL doctor. I’m not a CLL patient. I work in Seattle. I’m at Swedish Cancer Institute and I’ve been lucky enough to be involved with a lot of wonderful things taking care of CLL patients. It’s been a pleasure to be here with you, Brian.

BK: John, you may not be a CLL patient but you’re a friend to CLL patients, so I’ve deeply grateful for that. You’ve done some really important research. There’s a paper here that talks about Maintenance Therapy in CLL. First, can you just take us a step back and explain what Maintenance Therapy is, why that might be desirable, what that means, and how that fits into the picture, and then what the findings were?

JP: I think it’s a very important concept for patients to know about. That doesn’t necessarily mean that what I’m going to say is right for every patient. But I think it’s important to know about. That’s the concept of getting to some sort of remission or control of your disease, and then following that with some ongoing, very tolerable, easily manageable treatment, for some prolonged period of time. The goal would be to hopefully improve how long it takes before the disease might come back or perhaps even work towards keeping the disease from coming back. So, this is not a new concept. It is relatively new to the CLL world, but it’s something that we’ve been doing for many years for patients who have indolent lymphomas, such as follicular lymphoma.

BK: And CLL is classified as an indolent lymphoma. I always say that, you know, we’re blessed because we’re both a leukemia and a lymphoma, which means we get the benefit of research both in the leukemia and lymphoma worlds.

JP: But it does confuse patients too, and it even confuses doctors. But, yes, it is an indolent lymphoma.

BK: Indolent means “slow growing.”

JP: Very slow growing. We do know that people likely will always relapse from their disease, but one of the major goals is to keep people happy and healthy for as long as possible. So, you know, if I’m a patient, I like that idea of understanding that if there’s some kind of ongoing treatment, as long as it’s not causing harm or causing me to feel bad, I might like a longer time until my next treatment. Now I want to be fair. We have to understand that everything we do has some degree of a side effect profile. Certainly, doing nothing is always safer from a side effect profile than doing some type of therapy. But if it’s manageable and tolerable. It’s not unreasonable in the right patient. I think that was a very important thing that came out of the maintenance approaches discussed here, at this meeting, was the idea of the higher-risk patients, patients with perhaps a little bit more aggressive disease that they might benefit from some ongoing treatment. Something we would again call maintenance therapy.

BK: I know in the past there’ve been some papers on using the monoclonal antibody Rituximab for maintenance in CLL. But that’s really never seemed to have taken off and I think there’s some evidence that some of the newer generations are actually approved now for maintenance therapy. Can you comment on that a little bit before we talk about some of the new data presented?

JP: Right, and I think that the new data that we will talk about is different than what you’re alluding to. So, more recently, even in fact in the last couple of years, we’ve adapted this same thing in the CLL community, from what we were doing in Follicular Lymphoma by giving periodic doses of an anti-CD20 antibody, as an example, perhaps a drug called Ofatumumab which is a second generation antibody that targets CD20 on the surface of B Cells. Those CLL cells are B Cells. So, the problem with that approach has been two-fold. Not that it can’t extend time to the next treatment or improve the time before you relapse, but the problem is you’re treating lots of people with a lot of drug that may not be something that that individual patient needs. That’s why alluding back to what we’re going to talk about is that the maintenance approach was in the high-risk patients who really can benefit from all that treatment. So, giving an ongoing therapy to perhaps very favorable patients, meaning with good chromosomal changes, without high-risk features may not actually be giving them a lot of benefit because they don’t necessarily need that. The other thing that we know is that, in those more favorable patients, if you don’t get maintenance therapy but your disease comes back, and you just get treatment at that time, you’re still going to do just as well, as opposed to those people who got ongoing therapy.

BK: So we did learn something new here and this was a German study, if I recall. Can you walk us through that and what group of patients they looked at, and what they found?

JP: This is a very interesting study, and I say “interesting” in its design. The design was for patients with high-risk features of chronic lymphocytic leukemia. So, those might be patients, and of course, the audience here knows, those are patients who have a deletion of the short arm of chromosome 17. We commonly call those 17P Deletion. Or they have an unmutated immunoglobulin heavy-chain variable-region (IGVH). Your audience is sophisticated enough to know about that now, but that’s a higher risk feature compared to those who are mutated. They also looked at evidence of minimum residual disease after initial therapy. So, patients could get any initial therapy – FCR (fludarabine, cyclophosphamide, rituximab), BR (bendamustine/rituximab), even fludarabine, cytoxan alone, some cytotoxic therapy and if they achieve complete remission.

BK: But not the more modern therapies? Not ibrutinib, or…?

JP: No. You could have done it that way, but it’s not the way it was done.

BK: Okay.

JP: If you got a complete remission, and of course, remember the value of complete remission is different for every single individual patient. But those patients where it might be most meaningful are those who get a complete remission, but still have evidence of disease either in their blood or their bone marrow, but a very sophisticated molecular level.

BK: This is the MRD negativity that you were talking about, Minimal Residual Disease.

JP: Right. So, if you can detect that, we do know that that is, even if you’re in what we call complete remission (meaning your CT Scan looks great, your blood counts have come back to normal), but if we can actually detect those cells down at the DNA level, the molecular level, the minimal residual disease, we know those people will relapse sooner. And frankly, if we’re trying to cure disease, we want to eradicate that. So in the right patients, where that minimal residual disease means something, and those might be people with 17P Deletion, unmutated IGHV, those examples, we know that those are higher-risk. With the MRD, those are the people that might really benefit from ongoing maintenance therapy to try and give them as long a remission as possible, and maybe even have a major impact in their survival. So, that’s what the German study did. It took those high-risk patients who have evidence of minimum residual disease and then randomized them to get either a placebo, (because that’s the standard of care after you get a remission, to watch people, and that’s okay) or they were randomized to get an oral agent that is gaining a lot of favor in the CLL world called Revlimid. Revlimid is not a new drug.

BK: Lenalidomide.

JP: Lenalidomide. That’s probably what I should have said. It’s a drug that we’ve been using in blood cancers for a long time and particularly in patients who have a different blood cancer called multiple myeloma. So, it’s an oral agent. At the doses studied in this trial, and most doses for most patients, it is very well tolerated. They were able to get that drug for a prolonged period of time and, compared to the patients who got a placebo, there was a dramatic improvement in what we call progression-free-survival (PFS). What that means is a dramatic improvement before patients actually have their disease come back. In fact, about an 80% reduction in the risk of progressing with your CLL if you got the maintenance therapy in these high-risk patients compared to those people who didn’t get anything.

BK: Over what period of time was that, roughly?

JP: Over a couple of years. Now does it mean anything? Well, you could argue that might be meaningful for each individual patient, but what we really want to know, after we follow people for a long time, that in those high-risk patients, maybe we’re actually going to help them live longer by doing this maintenance type of treatment.

BK: That’s the overall survival number.

JP: That’s right. We won’t have that data for many years, unfortunately, because again, people will live for a relatively long period of time no matter what you do…

BK: Even with the placebo treatment…

JP: So we’ll see, but there’s a chance that this kind of approach, in the right patient, high-risk, evidence of minimum residual disease, ongoing maintenance therapy may actually extend their overall survival.

BK: Lenalidomide is a little different than any of these other CLL drugs in it modulates the immune system called an IMiD for immune modulating. Can you explain a little bit about that, I mean, how it works or what, and I don’t think we fully understand really how it works?

JP: We have a sense. You know we’ve been hand-waving with this drug of how it works for many years actually. But what we do know is that it changes what we call the microenvironment where these CLL cells like to live, so lymph nodes, bone marrow, as an example. We know that it’s just not those cells that are hanging out there. It’s that the environment where those cells hang out is allowing those CLL cells to live there. The environment is not putting a stop to their existence in the bone marrow. So, what Lenalidomide can do is it alters the immune properties in the local microenvironment where CLL lives. And actually, if you can improve the health, and that’s the way I like to think of it, improve the health of the environment around the CLL cells, then the CLL cells can’t exist and they will die.

BK: There’s been problems with this drug in the past, tumor flare, blood clots, fatigue, secondary cancers, low blood counts and other…what’s the experience been? Are those that’s been on higher dosages, or those, can you help us through the adverse events because you are comparing, like you say, nothing to something.

JP: Right, and it has to be like I’ve said “tolerable,” otherwise it’s not worth it. You got to live life, right? But I will say that in this Trial, the data that we have, and the early data suggests that it is very tolerable and largely because it’s not used at high doses. So, the way the Trial worked was to start out at a low dose, 5 milligrams. If you did fine with a daily oral pill of 5 milligrams, after the first month you could go to 10 milligrams. And, in fact, everybody was able to tolerate to 10 milligrams. Then if that did well, people might go to 15 or so, and escalate based on how they were responding to it to eliminate their minimum residual disease of their CLL. But at these doses, problems with blood counts were minimal. Patients did have increased problems with blood clots. Now to be fair, the biggest reason for that we know that if you take this drug, Lenalidomide, that if you just take an aspirin a day that will largely alleviate any risk for blood clots. So, if you do this, if you go to your doctor and say “I’d like to explore this idea,” don’t take this drug without a daily aspirin at a minimum. And, if you take this into account in the lower doses, a little bit of prophylaxis, maybe with aspirin, actually it looks to be that it will be very, very well tolerated. But again, I would suggest that this is really data that we really want to always think about for the patients who might really need it.

BK: Secondary cancers and infections…was that higher in the treatment group?

JP: Well you know at these doses, and then patients, the infections weren’t worse, they were no different really compared to those people who didn’t get the drug. Secondary cancers is an interesting concern but we have to follow people for a lot longer to know if that’s going to be an issue here or not. There has been concern about lenalidomide, this drug, and perhaps when you alter the immune system as this drug does, I talked about it in the environment of the bone marrow, that maybe you’re going to cause perturbations or changes that suggest that you might get another kind of cancer. I think the data is pretty clear now though in the myeloma community that this drug probably doesn’t provide a significant increase at all in second cancers. We do need to find out if that would be potentially a risk here, by having a much longer follow-up.

BK: Any final thoughts on the maintenance issue or anything else from ASH that you want to share with the CLL community.

JP: Well you know it’s interesting, of course, you and I have done this annually for many years now, as you have with many other investigators and I’m sure they all will say the same thing. Every single time we come to this meeting, we walk away with really an incredibly positive feeling for our patients because we’re making huge strides to improving their lives every single day. Not the “we,” meaning me, I just mean the CLL world and community and patients are a very important part of that. This is a positive time. We’re doing good things. I really do believe that someday this will be something that we’ll be talking about as something that we’ve had such a major impact on survival, that we’re going to focus on other leukemia’s and things more, as we move forward.

BK: Dr. Pagel, thanks so much for what you do for the community.

JP: Brian, my pleasure, thanks. Nice to be with you.

Enjoy the video interview!

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Dr. John Pagel is Chief of the hematologic malignancy program at the Swedish Cancer Institute in Seattle, WA.

Dr. Brian Koffman, a well-known doctor, educator and clinical professor turned patient has dedicated himself to teaching and helping the CLL community since his diagnosis in 2005. He serves as the unpaid medical director of the CLL Society Inc.

Originally published in The CLL Tribune Q4 2016.