Dr. Nicole Lamanna:
Welcome to The ASCO Post Roundtable Series on Treatment Approaches to Relapsed/Refractory CLL. I'm Dr. Nicole Lamanna, I'm a Professor of Medicine and CLL specialist at Columbia University Medical Center in New York, and joining me today are two of my esteemed colleagues. If you can each introduce yourself, that would be wonderful. John, do you want to start with you?
Dr. John Allan:
Yeah, thank you, Dr. Lamanna. I'm John Allan. I'm here in New York City as well at Weill Cornell where I'm an Associate Professor of Medicine and a lymphoma CLL specialist.
Dr. Inhye Ahn:
And I'm Inhye Ahn. I'm an Assistant Professor at Dana-Farber Cancer Institute in Boston.
Dr. Nicole Lamanna:
Again, very happy to have you both here to do this. Today, we'll be discussing the treatment and management of relapsed/refractory chronic lymphocytic leukemia with three patient case studies. And really, we hope this will be informative. Given the multiple treatment options that we now have in patients with CLL, hopefully this will go through different cases and go through, in more detail, the potential options given all that we have now today.
To start our conversation, though, we're going to start on a focus of a case in front-line treatment for CLL before we hit the relapsed/refractory cases. This is a patient with a deletion 13q and trisomy 12 and unmutated IGHV. This is ML. He is a 71-year-old gentleman who presented in 2020 with symptomatic CLL and then he was monitored for a period of 4 years. He then developed progressive fatigue and weight loss, some splenomegaly, and bulky lymph adenopathy to lymph nodes 5 to 7 cm. He has a good performance status and adequate renal function. His white count is elevated to 113, his hemoglobin is 10.3, his platelets are mildly reduced to 105. As I said, he is unmutated, he has a TP53 wild-type, deletion 13q and trisomy 12. No deletion 17p.
Obviously, there are many options to consider for front-line treatment now for patients with CLL, and I'm going to list a bunch of questions, but I think what we can do is bulk them and discuss the different options, and partly the answers, given so many treatment options. One is patient preferences for treatment, I think we need to talk about that, and their prognostic features. Is this relevant anymore when we talk about prognosis and their genetics, given the treatment options? And how do the comorbidities of the individual patients play a role in potential treatment options? Obviously, we're going to talk about, I think the main question we always talk about, is time-limited vs continuous therapy for this particular patient and what may be appropriate. And then we can even discuss and change the genetics of the patient a little bit. Just to start with that, maybe, Inhye, do you want to talk about this particular patient and what might be your consideration for one of the front-line or front-line options for this patient?
Dr. Inhye Ahn:
Yeah. We currently have a lot of front-line options, so when I present these options, I talk about two simple concepts. One is time-limited and the other one is continuous. I list multiple time-limited regimens underneath that bucket. That includes the 12 cycles of fixed-duration therapy with venetoclax and the obinutuzumab or 14 cycles of fixed-duration therapy with the acalabrutinib/venetoclax, with or without obinutuzumab. The continuous treatment really comprises of a BTK inhibitor, usually the selected BTK inhibitor such as acalabrutinib and zanubrutinib. And the way to choose between these two options is really based on the patient's preference and their acceptability of the side effect profile.
I think for this specific case, the patient can benefit from either continuous BTK inhibitor or VO, which is venetoclax/obinutuzumab, or the triplet therapy with acalabrutinib, venetoclax, and obinutuzumab. The reason that I'm removing acalabrutinib and the venetoclax combination from this list for this specific case is because of the unmutated IGHV. In the AMPLIFY study, their outcome was not as great as those with the mutated immunoglobulin gene, so I would be hesitant about giving acalabrutinib and venetoclax for this patient population.
Dr. Nicole Lamanna:
John, do you want to talk about the data a little bit with AMPLIFY? Because I think many may not know, not only the data, but more importantly that the combination now of a BTK and a BCL2, although not yet quite FDA approved, we're waiting, that it has been incorporated into the NCCN guidelines. So maybe you could talk a little bit about that data and also talk about this patient and what you would consider as well in addition to what Inhye said about the potential treatment options for this patient.
Dr. John Allan:
Yeah. So the AMPLIFY study, as touched upon, was a really important study for us as treating physicians to really know how to place doublets and triplets and how do we start to incorporate them in patient care. As a reminder, this study was acalabrutinib/venetoclax vs acalabrutinib/venetoclax/obinutuzumab vs chemotherapy, which was either FCR or BR, and it was a randomized 1:1:1 clinical trial. All patients were included except those with the deletion 17p, and because a chemotherapy arm was being randomized to, most patients were relatively young and fit, and I think the median age was somewhere around 60 or so.
And so what we now saw at about 3 years of follow-up is that the acalabrutinib/venetoclax–based approaches both beat out chemotherapy in terms of progression-free survival, and in fact, some trends, maybe, towards overall survival depending on how you look at the data with COVID and et cetera involved or not. At the end of the day, though, we saw that both the acalabrutinib and venetoclax regimens worked great. They offered now a new fixed-duration approach over just venetoclax/obinutuzumab.
What we saw, though, was that MRD rates were relatively low with the oral doublet acalabrutinib and venetoclax. And that gets to Dr. Ahn's point where she preferred acalabrutinib/venetoclax/obinutuzumab for this patient based on that unmutated IGHV status because those patients really seem to benefit greatly from improving the MRD negativity status. We saw with the triplet it went from somewhere, 30% or so with the oral doublet, upwards to close to 85% or so of patients with the triplet. The ones who mainly benefited were those with the unmutated IGHV status, and that's likely due to that clonal kinetic, that we know those patients have higher rates of growth, and therefore if we can get deeper remissions with those patients, they will remain in remission longer. And likely that's reflecting in that MRD differential between these two groups.
And I agree, I think these higher risk types of patients, if we're offering fixed-duration, we should try to offer them the best approach that's going to get them off therapy for the longest period of time. And I do agree that I think we are in an era now where we are going to start to incorporate that mutational status again into our approach when we think about the patients and depending on the type of fixed-duration that we give, whether it's oral doublet, triplet, or venetoclax/obinutuzumab.
Dr. Nicole Lamanna:
That's a really good discussion. I think one of the questions that I want to pose to both of you is obviously the focus of time-limited has been increasing since the availability of the BTKs when we started with continuous therapy. Now that there are this data with triplets, do you think that the individuals that we're going to be offering triplets to will be mostly those individuals who, let's say, are unmutated or higher risk? Or do you think that the notion of increased toxicity with the triplets, providers might say, "You know what? I think, even though the PFS might be shorter, given your comorbidities, maybe a doublet is enough for now." Do we still have to factor in some of these other issues in addition to just MRD status and progression-free survival in these patients given that some of them might be older in addition?
Dr. Inhye Ahn:
Yeah, these are really good points. The study is not powered to look at the IGHV mutation or unmutated status or the patient comorbidities, so I don't think we're going to be able to answer that question directly. I think it is a fair argument, though, to use a time-limited all-oral therapy for older patients with a lot of comorbidities, because it should be better tolerated. Especially in the AMPLIFY study, the AVO triplet was associated with really high risk of high-grade infection. I believe about a quarter of the patients treated with the triplet regimen had grade 3 or higher rate of infection, which is a substantial number. That's 1 out of 4 patients.
Also, I want to highlight that in this specific case, the patient had a borderline lowering of the creatinine clearance, I think it was 60, and in the current venetoclax package insert, the cut-off is about 80. So the patient does have decreased eGFR. So choosing VO may require hospital admission while using A plus B because it has a little bit of BTK inhibitor lead-in before introduction of the venetoclax that would take away the requirement for the hospitalization for this specific patient.
Dr. Nicole Lamanna:
John, do you want to add some comments into this as well, focusing on the double/triplet issue?
Dr. John Allan:
Yeah, I think, as stated before, we don't really know exactly how to employ these because obviously adding in the obinutuzumab does increase that infection risk. We see higher rates of grade 3/4 infections in this particular study, which was done at the beginning of COVID. And when we didn't have therapeutics, we didn't know how to manage patients as well and we didn't have immunizations, there was, in fact, increased deaths in the arm that had the obinutuzumab over the oral doublet. So clearly adding all three of these drugs together can increase toxicity and it is something you need to be very cautious with.
And in particular, this patient, who is now in their 70s with some impaired creatinine clearance, this is somebody that the AVO answer is not just a blanket answer, "unmutated IGHV, that's who you give it to." You really do have to think about their fitness on top of that. And we are still struggling to understand who it is, but it does seem pretty clear that these higher risk patients, the unmutated IGHV patients, do seem to gain a benefit from the addition of that maximal therapy.
Though, with that said, we've never really seen an overall survival difference between those two arms. You do get deeper remissions, you do remain off therapy probably longer, but at the end of the day, the survival difference between triplet and doublet hasn't really necessarily shown any difference, and so it's not wrong to use any of these approaches for any specific type of patient. It depends on how you feel about a fixed-duration approach. I do think that we should try to maximize time off of therapy if we're going with that approach. But again, case specific. An older patient may not need to be off of therapy for 10 years, whereas a 50-year-old, it might be important for them to be off of therapy for 10 years. So it's always case dependent.
This study was helpful in showing that there can be improvements with the triplet with the obinutuzumab added, but it's still somewhat uncertain how to absolutely employ this based on specific risk factors. And it's still coming down to a discussion, shared decision making, being very clear and understanding what these risks look like and what the end result might be, of, do you take a risk of increased toxicity for potential longer term benefit off of drug? And that's really the trade-off that we're thinking about and something we need to consider.
The other thing about this patient specifically, though, is the disease bulk that they have where I think an AV or an AVO approach is maybe better, or in my practice, would be offered maybe over the venetoclax/obinutuzumab approach because that debulking ability of that BTK inhibitor is very important to mitigate that lysis. Particularly, as Dr. Ahn stated about the creatinine clearance being a little bit lower, we want to mitigate TLS risk as much as possible. And with venetoclax/obinutuzumab, you start with the obinutuzumab, there's still lysis risk there. There's still a lot of issues. This patient has an elevated white blood cell count, they have bulky disease, this is somebody you are going to be worried about, and the AV-based approaches kind of mitigate that and really take away that tumor lysis risk when that venetoclax finally comes on.
Dr. Nicole Lamanna:
I know we have a little bit of time left. I want to switch this up just because it's a really good discussion. What about if the patient had a 17p or TP53. Knowing that the AMPLIFY data did not address those because of the chemoimmunotherapy arm and knowing that the ELEVATE data, when we added obinutuzumab to acalabrutinib in patients with 17p also did not make a difference, how do you feel about this particular? So if the patient had a 17p or a TP53 mutation, do you feel any differently about the treatment recommendations? Would you offer a time-limited approach, AV or AVO still for this patient? Or continuous therapy?
Dr. Inhye Ahn:
I will tackle this question first. So I would offer the same list of up options for patients with TP53 aberration and would be very explicit about the expected PFS being relatively on the shorter side for the VO. And also the data from the AVO arm of the AMPLIFY study did not include the TP53 aberrant population. But at the same time, there is a phase II study with a 4-year follow-up testing AVO in this specific population, and the 4-year PFS was approximately 70%, which is encouraging. So I think AVO or VO is a good time-limited option for patients with TP53 aberration as well as continuous BTK inhibitor. As Dr. Lamanna pointed out, I don't offer CD20 monoclonal antibody addition to the BTK inhibitor because of the lack of benefit in PFS in the ELEVATE study.
Dr. John Allan:
Yeah, and I would agree with that. If we are thinking of offering one of these two approaches and there's a del(17p), despite the fact that we don't have the phase III data in this study, we do have the study Dr. Ahn was speaking about from her group there with Matt Davids that he led looking at AVO in these high-risk patients, and that 4-year 70% fixed duration, technically a fixed-duration approach, most patients did stop, of 70% looks really good. With I plus V and the CAPTIVATE study, which included del(17p) patients, those patients who stopped after the fixed duration have a median PFS of about 4 years. So the triplet seems to numerically add some effect to these highest-risk patients. They can get deeper remissions, again, translating into higher MRD rates, and it looks like they may have improved outcomes.
Now, with that said, even in that study, though, those patients with CRs and deep MRD-negative remissions were still relapsing. And so it still comes into the question, should we talk about continual therapy for these patients? Again, an overall survival has never been shown to be shorter for any fixed-duration patient with a higher-risk disease, but it is something that I do think about, and we know the 4-year PFS on a continuous therapy BTK inhibitor in those patients is about 75%. So you kind of get the same end point, but one is a fixed duration with maybe more toxicity. And again, it's going to come down to that type of patient, those risk factors.
This patient's age is 70 here, 71, I think, and with bulky disease, and this is somebody that is kind of getting onto the cusp of, "Do we give maximal therapy with that increased toxicity?" And there is no problem to address another one of these questions to offer a continuous therapy, just BTK inhibitor, just based on where they are in their stage of life, and in particular, if there were some higher-risk disease features, because we know those patients can do very well for a long period of time.
Dr. Nicole Lamanna:
Yeah. I agree with you. I think that's a great option for an older patient, too, which, just to conclude, means that we have lots of great options for our patients with CLL, which is good to know. There are many considerations for initial therapy for these patients with CLL, including patient preferences, their comorbidities, and also their genetic and prognostic markers that we just went through.
And obviously current practices means that patients can still be offered, depending upon these discussions, continuous therapy or now time-limited therapy now with the addition of not just venetoclax/obinituzumab, but a BTK plus a BCL2 inhibitor. And then I think the discussion, from what you all are saying about triplets, sounds like very good options. Still need a little bit more data about who might be the best people for triplets. But it sounds like, with more studies and more randomized data, hopefully we'll get some clarity about who might be the best people and taking into consideration the potential of increased toxicity and infectious complications in our patients.
So important to include all of that in your discussion in the front-line treatment options for patients with CLL, both for considerations that include their preference as well as their disease characteristics and their comorbidity. So with that, I'd like to conclude. This brings us to the end of this case. And please see other segments for further discussion about the latest research in CLL or visit ascopost.com.
