Therapeutic Approaches for CLL



Nicole Lamanna, MD: I think many of us are moving away from chemoimmunotherapy in the unmutated group. But to be fair, I think that it also is a patient preference issue, as Steve was saying, with regards to types of therapy and duration of therapy. Obviously, we’re going to discuss lots of therapies where we’re looking at truncating therapy. But for now, patients are staying on ibrutinib theoretically until they progress or they have a toxicity. So, having that conversation, they may still preferentially decide that versus that. But I think in general, I agree with Steven about the unmutated IGVH.

William G. Wierda, MD, PhD: The Germans have done work in terms of categorizing patients as go-go fit patients, slow-go, or the no-go patient population. They’ve also used a comorbidity index in their trials for inclusion criteria. So, are those things useful? Do we use our clinical judgment when assessing, or are there objective parameters that we’re using...?

Nicole Lamanna, MD: I think we do something similar in the United States. Generally speaking, we’re looking at their comorbidities. They formalized in the studies that they ran. But we’re looking at their renal function and their other medical problems: coronary artery disease, diabetes, hypertension, and so on and so forth. So, in choosing particular therapies, you’re going to be choosing those therapies based the comorbidities of your patients and what their renal function is.

So, I think that’s very similar. We have data showing that clearly some of the therapies that we’ve given, as Steve pointed out—the median age being in the mid-70s—are very active and just may not be very tolerable in our older patient population with these comorbidities. You lose that benefit of the efficacy in a very myelosuppressive regimen per se. So, you’re picking based on their comorbidities. Obviously, the TKIs have shifted that a little bit because now you can give ibrutinib to all-comers, and albeit it does have side effects that I’m sure we’re going to discuss. It’s still more manageable than chemoimmunotherapy. And so, all can actually benefit from a TKI. You’re going to discuss whether or not patients want to stay on indefinitely, at least right now. So, oral therapy versus, depending upon their prognostic markers, chemoimmunotherapy. But I think we do something similar, we just base it on, as Steve said, our clinical experience, our judgment, and the comorbidities of our patients’ renal function.

William G. Wierda, MD, PhD: Dr. Ma, the FISH results in using 17p is already in the guidelines that we use, NCCN for example, to direct therapy. Mutation status, immunoglobulin, heavy chain, IGVH mutation status hasn’t made it into those guidelines. Do you think it’s time that we should have the discussion and bring that factor into the algorithms that are developed as guidelines for therapy?

Shuo Ma, MD, PhD: Yes, I think that would be very helpful. That will help with the reimbursement. But from the necessity point of view—based on the analysis of several very large randomized studies, for example, CLL8 study and CLL10 study—and also from the novel therapy point of view, the IGVH-mutated versus unmutated patients do have really different outcomes. And IGVH-mutated patients seem to benefit the most from the immunochemotherapy. So, data from your center, MD Anderson, and also from the CLL8 study definitely show that for young fit patients with IGVH-mutated status, there seemed to be a plateau after a number of years. There are a group of patients, almost about 50% would you say? Those patients seemed to have a very prolonged profession-free survival, and there is maybe that potential of cure for those patients. So, there are a lot of efforts in trying to develop new combinations, trying to reduce the potential toxicity from FTR, and to improve upon the benefit of the efficacy. I think making IGVH mutation tests in the NCCN guideline would definitely help to, for us, better guide patients because it’s a very important predictive factor.

William G. Wierda, MD, PhD: Speaking of making improvements on what one would consider a standard chemoimmunotherapy regimen, FCR, Matt, you presented at this meeting your work with the iFCR regimen. Maybe you can explain to us the rationale for that and what you’ve seen with the report that you presented at this meeting.

Matthew S. Davids, MD, MMSc: We’ve been inspired by the long-term results that we’ve seen with FCR alone from your center and others with mutated IGVH, patients having very durable responses. However, it’s not durable response for all so even the mutated IGVH patients need improved regimens. Moreover, patients with the unmutated IGVH only had about a 10% progression-free survival long term. And so, we think there’s a lot of room for improvement there.

The idea with our study was to add ibrutinib to FCR for a 6-month course of combination followed by 2 years of ibrutinib maintenance. And although it’s a frontline study, we have an early readout that is using the MRD-negative status of the patients at the end of the combination. We’ve seen very high rates of MRD-negativity, which we do think will translate into prolonged progression-free survival for these patients. So far, the results of the study look encouraging, but it’s still early. It’s a 35-patient study so far. We’re extending it to 85 patients where we’ll be able to say something a little bit more meaningful. I can highlight also that in the same session, your center presented really exciting data for ibrutinib with FCG and GA101, or obinutuzumab. It focused on the mutated IGVH patients, and I think that’s also a very promising approach.

Steven Coutre, MD: Your results are a little surprising to me because it seems from the MD Anderson data with FCR that the mutated patients who achieve MRD negativity are really the ones who are benefiting. And of course, you don’t know if you’re going to be one of those patients when you start therapy. The mutated patients who don’t achieve MRD negativity dropped out like everybody else. So, you employ a strategy of adding a novel agent, and I wouldn’t take priority to think that adding ibrutinib to FCR is going to get you more MRD negativity. Your preliminary results suggest so. I would think perhaps using obinutuzumab instead might. I think it will be really interesting if those studies continue, to see if they do achieve more MRD negativity and if that does translate to prolonged benefit. But the MD Anderson studies and the German studies are very mature studies. It’s hard to collect that kind of long-term data to really know if this is the way to go.

William G. Wierda, MD, PhD: I have a particular interest in minimal residual disease and looking at our chemoimmunotherapy regimens, and now our non-chemoimmunotherapy regimens. I think one of the early parameters also that will be interesting that there are not a lot of data for is time to MRD relapse, and I think that will be an earlier indicator than waiting for progression-free survival because it does precede clinical progression predictably by at least a couple years. So, I think we can collapse down to the timeline in terms of gaining useful information in the frontline setting even when we get these deep remissions, if we’re looking at more sensitive methods for MRD and also looking at MRD time to relapse.

Steven Coutre, MD: But what will that mean? OK, it means that you will get clinical relapse afterwards, and we don’t know. It’ll be regimen dependent probably on how long that might take. And of course, the question you want to know is, do I need to do anything about it or are you fine just doing something when you have a reason to treat again? I think that’s the crux of it.

William G. Wierda, MD, PhD: Developing curative strategies is the approach now for the patients who have a mutated group. The trial that Matt referred to is the IFCG trial, and it will only enroll patients that had a mutated IGHV gene. So, we’re looking for MRD relapse in that study. We have some baseline data also with regard to FCR in terms of the incidence in MRD relapse.

Steven Coutre, MD: What is that?

William G. Wierda, MD, PhD: A longer term time to MRD relapse. As I mentioned, it’s an earlier indicator and that study, the historic FCR where we did all the prognostic factors and prospectively looked MRD, is still maturing. So, we’re still working on the follow-up from that trial. But I do think that MRD relapses is a potentially important parameter to look at, particularly if we’re talking about developing these potentially curative strategies and we’re not wanting to wait for these follow-up times that we need to monitor patients for in the frontline setting.

Steven Coutre, MD: Well, it sounds like it would be more helpful to tell you that you’re actually not curing patients.

Shuo Ma, MD, PhD: What I really like about the IFCG study is the short-term of duration FCR. So, we know the FCR can give some patients a very long duration of response, but the problem is just always the concern of the 5% of patients who may develop secondary malignancies in the marrow, such as MDS or acute myeloid leukemia. If we can use some strategy to improve the efficacy but at the same time trying to reduce the potential long-term toxicity, I think that strategy is really appealing. So, that’s why I really like the design of your study to ISCG, which only utilized 3 cycles of FCG combined with ibrutinib. And then, there is the MRD-tailored approach after that. So, your patient’s MRD-negative. MRD negativity is your endpoint for treatment so you can use continued combination of ibrutinib with obinutuzumab to achieve the MRD-negative status, or use a prolonged use of ibrutinib. So, I think MRD-tailored approach with a shortened duration of chemotherapy is really the way to go.

Transcript Edited for Clarity

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