Evolution of the treatment paradigm for patients with chronic lymphocytic leukemia (CLL)

DR WIERDA: CLL has evolved from a basic science perspective, as well as a clinical perspective. More fundamentally from a clinical perspective, I think, over the last 3 to 5 years. We’ve done a lot of work with chemoimmunotherapy in the past, and with that strategy we were able to achieve a fair proportion of patients in complete remission, and patients had a relatively durable treatment-free interval, and in the chemoimmunotherapy era we were able to identify a subgroup of patients particularly who benefit from chemoimmunotherapy. Those are patients who are young and fit and able to tolerate the FCR regimen, who have a mutated immunoglobulin gene. More than 50% of those patients are progression free more than 10 years, and maybe those patients are cured.

And that transitioned into an era of small molecule inhibitors, particularly ibrutinib, but there were others that were developed subsequent to the development of ibrutinib, which is a BTK inhibitor, came the PI3 kinase inhibitor idelalisib, which was a little bit more challenging in terms of the side effects and toxicities. And then most recently, in terms of small molecule inhibitor development, has been venetoclax, which is a Bcl-2 small molecular inhibitor. With ibrutinib and BTK-based therapy, we were able to achieve excellent disease control. But patients didn’t get in a deep remission.

We went into an era of managing patients, first in the relapsed setting, and then in the front-line setting, with BTK inhibitor-based therapy, which was very effective at controlling disease in the relapsed setting, also in the front-line setting. Patients needed to remain on treatment because patients didn’t achieve a deep remission. And then we went into an era of venetoclax development. Now venetoclax is a more potent drug in terms of disease reduction and achieving a deeper remission.

And most recently we have done trials and have presented our data on combinations of treatment, combinations of BTK plus Bcl-2 small molecule inhibitor. And with that strategy, and with venetoclax-based strategy, we’re able to achieve very deep remissions, where a high percentage of the patients are MRD negative in the bone marrow. They’re achieving complete remissions, and so we’re back to having a discussion about fixed-duration treatment, deep remissions, and having patients off treatment.

I think with time we will have an understanding of if the same principle of potential cure with chemoimmunotherapy also applies to small molecule inhibitor-based therapy for the patients with a mutated V gene, also potentially for patients who have an unmutated V gene. But we’ve come full circle now back to an era of achieving deep remission, giving fixed duration. With the new programs that we’re working on, we’re aiming to give a shorter duration of treatment to achieve a similar effect in terms of depth of remission, which should translate into a long treatment-free interval for most patients.

Biomarker assessment for patients with newly diagnosed CLL

DR LOVE: Another thing that’s very relevant clinically that’s happened over the last few years, that’s been very interesting to us, kind of, as a CME group trying to figure out what people need to know with so much stuff going on, is the issue of the workup of the patients and the related biomarkers. Because it seemed like in the past there were just so many different biomarkers that you could, and people were drawing, but as we started to hear more about predictive biomarkers, it kind of seemed like there were fewer and fewer that were really that critical. From your point of view, for the general medical oncologist, community-based practice, typical kind of case, what advice would you give about biomarkers?

DR WIERDA: The biomarkers, there are some that are critical and important to evaluate. We need to know if a patient has a 17p deletion. And that’s because even though we have very effective treatments for patients with 17p deletion, the progression-free survival tends to be shorter for that subgroup of patients. Now it’s much better than it was with chemoimmunotherapy-based treatment, but it is shorter than patients who don’t have the high-risk feature of a 17p deletion or a complex karyotype. We need to know it because it affects our view and planning long term for our patients’ therapy and strategy for therapy. We’re less inclined to be comfortable with getting patients off treatment, if they have high-risk features, where we would expect for them to have proliferative disease that would return in a treatment-free period.

17p deletion is important. Mutated TP53 is an important feature to know about patients, and whether or not they have a complex karyotype is also important because that’s also a marker of a shorter remission duration and shorter progression-free survival on the small molecule inhibitors.

DR LOVE: Just by asking investigators we try to tease out how people view these things, and the other factor we’ve heard a lot about is IgVH mutation status. And we’ve actually instructed — I don’t know if you remember, I guess about a year and a half ago, you were part of this working group we had with a bunch of general medical oncologists at Florida Cancer Specialists, in, kind of, trying to get down to the nitty gritty of what all this really means. And we kind of began to start to look at algorithms based on TP53, del(17p), IgVH and karyotype. It seemed like those were the factors that were actually driving the decisions.

DR WIERDA: They were. And IgVH mutation status is still important if you have a young patient who could potentially receive FCR. And that’s because, as I mentioned, about 50%, 55% of patients who receive FCR, who have a mutated V gene, will be progression free more than 10 years and potentially cured of their disease.

We have clinical trials that are aimed to give a shorter duration of chemoimmunotherapy and our combinations with small molecule inhibitors and chemotherapy with the objective of giving less chemo and achieving a higher proportion of patients who are MRD negative, in remission, and hopefully boosting that 50%, 55% progression-free survival more than 10 years higher.

Therapeutic approach for older patients with CLL; IGHV mutation status in treatment decision-making

DR LOVE: That subset you were just talking about, the younger patient who could tolerate FCR with IgVH mutated disease, of course, del(17p), P53 negative, something that we’ve been talking about for a long time. We’ll talk about some of the data that came out over this past year related to that. But before we get into that, I’m curious, does this idea of IgVH mutation status affect the way you make decisions for older patients who are not eligible for FCR? Are you more inclined to still use BR or obinutuzumab/chlorambucil or some other chemoimmunotherapy regimen, even if it’s not FCR?

DR WIERDA: For myself, personally, I don’t use chemoimmunotherapy for those patients. And because I think there’s toxicity associated with it, there’s the potential for second malignancies, MDS, AML. We have a lot of extremely good treatments that are relatively well tolerated now, and we’ll talk about some of the newer data with the small molecule inhibitors. I think we can achieve deep remissions with nonchemotherapy treatment. For that particular population, I’m not really considering chemoimmunotherapy. Immunoglobulin mutation status is less important to me when making a treatment decision.

I still find value to checking the immunoglobulin V gene mutation status because it does correlate with time to treatment. And if a patient has an unmutated immunoglobulin gene, I tend to expect for them to need treatment within a few years. Most of those patients will progress and will need treatment. The patients with a mutated V gene, that’s not necessarily the case, and you can have those patients being observed for many, many years without needing any treatment.

DR LOVE: That’s really interesting. When you think about what you just said you don’t use first-line chemoimmunotherapy in the rest, well the rest is almost everybody. I guess my question is how long have you been making that statement? When did you go to the point where you just abandoned chemoimmunotherapy other than this subset?

DR WIERDA: It’s been probably the last 2 to 3 years. All of our clinical trials are designed for non-chemoimmunotherapy-based treatment for patients over 65. We do not currently have a chemoimmunotherapy protocol — a protocol with chemoimmunotherapy for patients over 65. It’s all small molecule inhibitor-based therapy. The trial that we do have that’s available with chemoimmunotherapy, again, is for younger patients, particularly those who have a mutated V gene.

We’ve even tailored down our options for trials with regard to chemoimmunotherapy to just that group that we know benefits from chemoimmunotherapy. For everybody else it’s nonchemoimmunotherapy small molecule inhibitor-based therapy.

DR LOVE: We’ll get into the granularity of the data that’s driven a lot of people to make that conclusion. You made it probably earlier than other people, but I think a lot of people did at ASH last December, for sure. I am curious though, before we start to dig into that, what you see as the current role of chemoimmunotherapy in relapsed disease? For example, BR?

DR WIERDA: I don’t think there’s a role for chemoimmunotherapy in the relapsed setting. We don’t use it. We use small molecule inhibitor-based therapy or clinical trials. We have a number of clinical trials. Right now, we are struggling with putting patients on our clinical trials because they’re doing so well with the small molecule inhibitor therapy they’re — we have limited numbers of patients who are failing those treatments and needing an alternative treatment. We’re having trouble enrolling on our clinical trials right now in the relapsed setting. None of them are chemoimmunotherapy-based options. They’re all non-chemoimmunotherapy-based options.

Case: A woman in her early 70s with CLL with deletion 17p, a p53 mutation and no IGHV mutation achieves a complete remission with ibrutinib and venetoclax as first-line therapy on a clinical trial

DR LOVE: That’s a good problem to have, as they say. Why don’t we get into some of your cases and start to pull out a little bit about how various data sets are affecting what you do. And I guess we could start with maybe 1 of the most interesting things I wanted to ask you about, which is what you were talking about, which is the combination novel strategy. It looks like that’s what happened with this 70-year-old woman. What happened there? It looks like she started out in June of 2017, so about 2 years ago.

DR WIERDA: Yes, so this is a 70-year-old patient who came to see me who had high-risk features when she presented. She knew she had high-risk features, and that was 1 reason that she sought an evaluation with us at Anderson. She had a 17p deletion by FISH. She had mutated TP53. She had a complex karyotype, and she had an unmutated immunoglobulin gene. And she had relatively aggressive, or progressive disease, where just during a short period of observation she had her white count that was rising. In fact, it doubled in the first 3 months of observation. And she was needing therapy when I saw her.

This is a patient with 17p deletion, mutated TP53, for whom we would not ever consider chemoimmunotherapy —

Implications of del(17p) and p53 mutations in CLL pathogenesis and for the selection of treatment

DR LOVE: Can I just pick up on 1 point? I was going to ask you before when you were talking about biomarkers if you could — because it came out at that working group we did, as a matter of fact. If you remember, the survey we did of those docs prior to that time, they weren’t as aware of the issue of TP53 as they were of del(17p). It’s interesting, this woman had both. Can you explain the genomic anatomy of what actually goes on if a patient has both of these?

DR WIERDA: Sure. On the FISH probes, when we probe for 17p, the gene that we probe for is TP53. If a patient has 17p deletion by FISH, they have a deletion of 1 of the alleles of the TP53 gene. That leaves an alternative allele, and in patients who have a 17p deletion most of them have mutation in the alternative, or the other allele that’s present there. It’s essentially a complete knockout of TP53. And those patients are not sensitive to chemotherapy. It’s a marker for genomic instability. They tend to get mutations. They tend to develop Richter’s transformation. They tend to have much more clinically aggressive disease.

It is important to check for mutations in TP53. If 17p is there, we expect TP53 to be mutated. Now there are cases where you don’t see 17p deletion, and you see mutations in TP53. And those also are important because they are higher risk compared to patients who don’t have either. And we would not give chemoimmunotherapy or chemotherapy to anybody who had a mutated TP53, even if they don’t have a 17p deletion.

DR LOVE: Before we get into the trial that she went into, I’m kind of curious what you would say in terms of options for a patient like this outside a trial today?

DR WIERDA: Right. Outside of a trial today, this patient should receive ibrutinib-based therapy. Or, we do have an alternative that was just recently approved, venetoclax-based therapy. Now, there are differences between those 2 options. We have a longer follow-up for ibrutinib-based therapy. We know the outcomes — long-term outcome’s a little bit better for ibrutinib. We know the toxicity profile and the long-term toxicity profile with ibrutinib. It’s more of a tried-and-true option for management for patients with 17p deletion.

But we essentially have 2 options. One is ibrutinib-based therapy, monotherapy. The other is venetoclax-based therapy. And the venetoclax-based therapy would be supported by a recent report of the CLL14 trial. Now, the venetoclax-based therapy is a fixed-duration treatment. This is 6 months of obinutuzumab with a year of venetoclax oral therapy.

Now, there are some features about 17p deletion, and we evaluate for minimal residual disease. If a patient like this were to receive a venetoclax-based therapy, I would be monitoring them for their response closely. I might be a little bit apprehensive if they had residual disease at the end of their year of treatment to stop treatment with venetoclax in that particular patient. But there are 2 options, ibrutinib- and venetoclax-based therapy for this patient.

Efficacy of venetoclax alone and in combination with obinutuzumab or rituximab

DR LOVE: And, if someone came in for a second opinion, and the first opinion said venetoclax alone, how would you feel about it? If the first opinion said venetoclax/obinutuzumab, how would you feel about it? And do you think an anti-CD20 antibody should be given in combination with venetoclax in this situation?

DR WIERDA: The original approval for venetoclax was for 17p in the relapsed setting. It was with monotherapy, and it was continuous and indefinite planned treatment.

Subsequently, there was a trial done for relapsed disease with venetoclax plus rituximab. We see a greater depth of remission, a higher proportion of patients who are MRD negative with a combination with a CD20 antibody. There hasn’t been a randomized comparison of monotherapy versus with a CD20 antibody, but my impression of the Phase II data has been that the CD20 antibody does add to the efficacy.

In the front-line setting, venetoclax has been tested with obinutuzumab, which is an alternative, probably more active, at least with chemotherapy, a CD20 antibody. In the randomized CLL14 trial, the experimental arm was venetoclax plus obinutuzumab.

If a patient had come to me with a recommendation for venetoclax monotherapy, I think that’s an option, but it would be better, I think, to treat this patient with a CD20 antibody because you would be expecting a higher proportion of those patients receiving that regimen to achieve a complete remission and to be MRD negative with that treatment.

I would probably recommend if the patient were to receive monotherapy — have a discussion, less of a discussion about fixed duration treatment, more of a discussion about indefinite treatment if we’re considering monotherapy.

I do think that there’s improved efficacy with the addition of the CD20 antibody, and it’s relatively well tolerated with a reasonable toxicity profile.

DR LOVE: That really led me to the question of in the past patients with del(17p) who progressed on BTK inhibitor or ibrutinib would get venetoclax alone second line. Would you still use venetoclax alone in that situation? Again, added to CD20?

DR WIERDA: I would add anti-CD20. Because I do feel that the addition of the CD20 does have a synergistic effect with venetoclax and does improve outcomes.

DR LOVE: Are there situations where you would choose to use rituximab combined with venetoclax as opposed to obinutuzumab? Or pretty much just obinutuzumab?

DR WIERDA: I like obinutuzumab because of the data with chemoimmunotherapy. It tends to be very effective at clearing circulating disease. It also is very effective at clearing marrow disease, more so than rituximab. There is a little bit more toxicity associated with it, particularly first infusion toxicity, with obinutuzumab compared to rituximab. But I do use rituximab occasionally. Not in the front-line setting, more in the relapsed setting.

DR LOVE: I was just thinking, are there any data or trials out there looking at subQ obinutuzumab?

DR WIERDA: Not that I know of.

DR LOVE: Are you using subQ rituximab? Or is MD Anderson in general using it?

DR WIERDA: We do not. I’ve had some issues with cutaneous reactions —

DR LOVE: Really.

DR WIERDA: — and tolerability with the subQ formulation, so I —

DR LOVE: Really?

DR WIERDA: — tend to give the IV, and I’ll give it, if it’s tolerated well the first infusion, then I will try to ramp it up to the 90-minute infusion rather than the 4-hour infusion.

DR LOVE: As long as we’re talking about alternatives, I’m curious about biosimilars. What are you doing about that?

DR WIERDA: I have not used biosimilars. We don’t have them included in our clinical trials. It’s hard for me to speak to that because I just don’t have that much experience with the biosimilars.

DR LOVE: How do you feel about biosimilar rituximab?

DR WIERDA: I think that obinutuzumab is a superior CD20 antibody. My preference would be to use that, either in the front-line setting or in the relapsed setting.

Phase II trial of ibrutinib with venetoclax for CLL

DR LOVE: Let’s hear about what happened with this patient. She went on a trial of ibrutinib and venetoclax. Which one? Which trial was it incidentally?

DR WIERDA: This was an — our own investigator-initiated clinical trial of ibrutinib and venetoclax. This is a trial that we initiated back in 2015/2016. It was a Phase II trial. We had 2 cohorts. We had a front-line cohort and a relapsed cohort. The front-line cohort we recently published in the New England Journal, and she participated in that clinical trial. That trial was 3 months of ibrutinib monotherapy initially to debulk the patients and bring their nodal size down. And we intended to reduce the risk of tumor lysis upon initiation of venetoclax with this 3 months of ibrutinib.

Patients then received 2 years, or 24 months, of combination therapy. And this trial, when we designed the trial, we didn’t really have a good idea about what the optimal duration of combination therapy was. We picked 2 years, and we said okay, if we’re going to do that, we’re going to be monitoring patients relatively closely for their response, and with the trial we would have a little bit better idea of what a fixed duration might look like for most patients. And so patients were evaluated every 3 months for response on that initial trial.

The trial was initially for 40 patients in each cohort, and then it expanded to 80 in each cohort, front-line and relapsed, and then 120 in the front-line cohort. We expanded it because we were so encouraged by the responses and the depth of remission. About 70% of patients at a year are MRD negative in the bone marrow. And most of those patients are in complete remission.

That trial we initiated several years ago. In parallel there was a relapse trial that the British, Pete Hillman, initiated. And they have reported similar outcomes to us in terms of the relapse cohort. They’ve also more recently added a first-line cohort.

Ongoing Phase II CAPTIVATE trial of ibrutinib with venetoclax as front-line therapy

DR WIERDA: And then there’s another clinical trial, which is a similar design to our trial. That’s called the CAPTIVATE trial. We reported the initial results of CAPTIVATE at ASH last year.

That trial is a little bit different design, the CAPTIVATE trial. It’s 3 months of ibrutinib monotherapy followed by 1 year of combination therapy, and then patients are randomized after that year of combination therapy, depending on what their MRD status is, for continued treatment.

DR LOVE: And what’s the current status of data for that trial?

DR WIERDA: That trial is ongoing. Patients have been randomized. It will be updated at ASH this year. We have information from that trial in terms of response after the year of combination therapy, and we know the proportion of patients who are randomized based on their MRD status at the end of the year. We don’t have any outcomes beyond the randomization.

DR LOVE: What’s the — not only the primary endpoint, but what’s, from your point of view, the major thing that you’re going to look at? I mean, I assume it’s not going to be long-term survival.

DR WIERDA: No, it’s not long-term survival. It’s a front-line trial. With all of these trials, overall survival is difficult to look at because patients are all doing so well. For that trial, as with our trial, the endpoints are MRD status at the end of the 1 year of fixed-duration treatment, the formal response, the iwCLL response at the end of that year, and then outcomes in terms of conversion to MRD negative for those patients who receive continued treatment and are MRD positive at the year of fixed duration. The MRD-positive patients get randomized to continued combination or monotherapy with ibrutinib. The MRD negative patients are randomized to ibrutinib monotherapy or observation. With that additional treatment, we will have some idea about conversion. MRD positive to MRD negative with continued treatment, or MRD negative to positive with either observation or continued treatment.

And really, probably MRD status and conversion, particularly in the blood, will be the next endpoint that’s a reasonable endpoint to evaluate and to have some understanding of what the regimen should be and optimal management of patients long term in the front-line setting with the small molecule inhibitors and combinations.

Relevance of minimal residual disease (MRD) as a clinical endpoint in CLL

DR LOVE: Any thoughts about using MRD status outside a trial setting? It certainly makes a lot of sense. The protocols are out there. What about using it right now in practice?

DR WIERDA: I think it’s an important endpoint. It gives me more comfort in terms of a fixed duration of treatment if a patient’s MRD negative. I’m much more comfortable with stopping therapy and giving them a treatment-free interval than I would be if the patient was MRD positive.

Now, we need trial data, and we need data to incorporate MRD status into our treatment algorithms and management of patients. We don’t quite have that yet, but I’m confident that in a few years we will, and that we’ll be treating and managing patients based on MRD status. I think that approach needs to be more data driven, and we just don’t have the data yet. But I’m confident that that’s the direction that we’re going.

We have traditionally looked at MRD status in the bone marrow. That’s not really feasible for routine practice/community practice, checking MRD status in the bone marrow. My opinion is that we need to develop and focus our attention more on blood MRD status and potentially develop more sensitive assays to look for MRD in the blood. And with that, we’ll probably be managing patients with the MRD status with treatment.

DR LOVE: If an educated patient, maybe the patient’s a physician or something, said, “I’d like to know what my MRD status is. I know maybe you can’t necessarily know for sure what to do about it, but I figured, I would like to know.” Is there any particular assay you’d suggest?

DR WIERDA: Currently there’s a couple assays. Currently, the standard assay has been the flow cytometry-based 4- to 6-color MRD. That can be done on the blood. It can be done on the bone marrow. It can be done at any time point, so you don’t need to have a pretreatment test — a pretreatment sample to assess for MRD status with that methodology. You could order, and you can get that done commercially, so to speak. There are third parties who will run an MRD test by flow cytometry for you if you wanted to order that.

There’s another NGS-based assay that is being worked on in terms of getting it FDA approved. That approach is a little bit greater sensitivity than flow-based assay. The flow-based assay gets 1 in 10,000 leukemia cells as the sensitivity for detection.

The NGS-based assay approaches 1 in a million or 1 in 10^-6. The limitation with the NGS-based assay is that it does require a pretreatment sample and then a follow up sample when you’re intending to evaluate for MRD.

But it is more sensitive, and we’re anticipating that it will be an FDA-approved assay in the future.

Effect of MRD status on outcomes in the Phase III MURANO trial evaluating venetoclax with rituximab for relapsed/refractory CLL

DR LOVE: Globally, I’m sure it depends a lot on the clinical situation. Maybe you can even pick a clinical situation in which we have data. But what do we know about the next 5 years, for example, after a patient becomes MRD negative and a patient who doesn’t become MRD negative?

DR WIERDA: We know from the MURANO data, which is venetoclax plus rituximab in the relapsed setting, that was a trial that was done with a fixed duration of treatment. That was 2 years of venetoclax, the first 6 months with combination of rituximab. At the end of the 2 years, everybody stopped treatment. And in the follow-up that we’ve had from that trial, the question has been who’s more likely to progress sooner at the end of that 2 years of treatment. And from the data that we have available so far, there’s 2 groups that are more likely to progress earlier when they stop venetoclax. One is patients who are MRD positive when they stop treatment. The second is patients who have 17p deletion.

Now that trial was done for patients with relapsed disease, so they were all previously treated. Those patients tend to be more proliferative than they are in the front-line setting, but that’s an example where one would have a discussion, I would have a discussion with a patient. At the end of the 2 years, testing for MRD. If they’re MRD positive, it’s easier to have a discussion about well, you’re tolerating this treatment, maybe we should continue it because I know if you stop it your disease will likely come back. Although there probably will be a year, 2 years before it comes back, if you stop the treatment. If you don’t stop the treatment, it’s probably going to be longer than that because you’re getting continued treatment.

DR LOVE: And for the MRD-negative patient? As time goes on, what’s the likelihood of re-treatment?

DR WIERDA: I mean, that’s going to be driven by clinical trials. And for all of our clinical trials, ibrutinib/venetoclax trial, all of the trials that we’re doing, we are monitoring for MRD in blood as an early indicator of disease that’s relapsing. We’re monitoring and doing serial blood testing for MRD relapse. In the chemoimmunotherapy era, we did that also, and we know that the median time between MRD relapse in the blood and clinical progression is about 2 years.

Now, there’s also a time period between clinical progression and need for next treatment. It gives us a bit of a lead warning for what’s going to happen, and it’s about a 2-year time between MRD relapse to clinical progression, and then sometime, a year or 2 years between, 6 months between clinical progression and needing next treatment.

The trials that we will do in the future, I think, will be interventions based on MRD relapse. We don’t have those set up right now, but those are definitely trials that we’re considering and planning for the future.

DR LOVE: In a patient who’s MRD negative, at 2 years, what’s the chance they’re still going to be MRD negative?

DR WIERDA: We don’t have that data. If we were to talk about chemoimmunotherapy, if a patient’s MRD negative at 2 years, and they have a mutated V gene, highly likely that they will stay MRD negative. If they have an unmutated immunoglobulin gene, that’s not necessarily the case. With chemoimmunotherapy we know even if you get a patient MRD negative, eventually their disease is going to return, and the median time to progression is 4 to 5 years. We know that with chemoimmunotherapy we have to generate a data set that gives us a similar view for the non-chemoimmunotherapy-based treatment.

Risk of tumor lysis syndrome (TLS) with venetoclax

DR LOVE: I want to hear a little bit more about what happened to this patient, particularly I’m kind of curious about how you manage TLS prophylaxis. You were saying that you start the ibrutinib first. You start the ibrutinib, and when you’re ready to start the venetoclax, do you look at their status at that point and plug them into the table, so to speak?

DR WIERDA: Right. For this particular patient, for all the patients, it’s 3 months of fixed-duration ibrutinib monotherapy. For this trial, we looked at everybody’s status at the end of that 3 months of fixed duration. And many of the patients were downgraded in terms of their risk for TLS when you initiate venetoclax. From a practical perspective, it’s really important to know who’s high risk for TLS, because you really manage those patients differently.

Patients who are low and medium risk, if their creatinine clearance is above 80, they are managed similarly, and you can manage them as an outpatient. But if they’re high risk, and high risk is defined by patients who have any lymph node size greater than 10 cm or lymph node size between 5 and 10 cm and a white count over 25,000, those patients really should be admitted for their first dose of venetoclax and first dose escalation.

If you look at everybody when they first went on that trial, for this particular trial, it was about a quarter of the patients who were high risk when they went on ibrutinib. At 3 months that was less than 10%. I believe it was about 8% at the 3-month time point, after 3 months of ibrutinib monotherapy. About 8% of those patients were high risk for TLS on initiation of venetoclax. We were able to downstage patients with regard to their risk and manage them differently, for the majority of patients who were high risk and got the 3 months of ibrutinib monotherapy.

DR LOVE: The practical question I had, and I’m not sure how it works out in terms of timing, is what do you do with a patient who gets a bump up of their white count because of the ibrutinib?

DR WIERDA: For the most part, many of those patients, particularly on this clinical trial, their white count was going down by the time they were starting on the venetoclax. If we’re talking about giving venetoclax plus obinutuzumab like they did in CLL14, those patients all get obinutuzumab the first month, monotherapy, same thing, —

DR LOVE: Ah.

DR WIERDA: — and then then venetoclax comes in after that first month of obinutuzumab monotherapy. Almost all those patients have a normal white count or a low — a white count that’s gone down at least below 25,000 with that combination. With our ibrutinib/venetoclax, most of the patients, their white count was coming down upon initiation of ibrutinib.

Prophylactic approaches for TLS associated with venetoclax

DR LOVE: What was this woman’s status in terms of her white count and her nodal size when she started the ibrutinib? And then when she got the venetoclax?

DR WIERDA: When she started the ibrutinib, she had lymph nodes that were 3 to 4 cm. Her white count was elevated, about 50,000. She was medium risk when she started. Her white count had come down by the time she started the venetoclax. I think she was low risk for TLS when she began venetoclax therapy at the end of that 3 months. And she was managed according to that risk.

I think a couple things that we probably should emphasize in terms of TLS and risk and management of patients with venetoclax. And those are that it’s important to know what the nodal size is before you start the venetoclax. And it’s also important to start patients on allopurinol, regardless of their risk, before they start the venetoclax. They should start allopurinol 3 days before they start the venetoclax. And you really have to know what category they fall in, particularly if they’re high risk for TLS before you start the venetoclax, because you do manage those patients differently.

DR LOVE: Can you talk a little bit about exactly what you do in the high-risk patient and where, if at all, rasburicase comes in?

DR WIERDA: Right. Patients who are high risk, most of them I will give rasburicase. Certainly I’ll give rasburicase if it’s elevated. If uric acid is elevated when they start. Everybody’s on allopurinol. Patients who have high-risk disease should be admitted for their first dose, and their first dose escalation with IV hydration, monitoring with serial labs. And most of them I will give rasburicase to, certainly those patients who have an elevated uric acid. And if their uric acid’s over 5, I will give them rasburicase.

Ongoing Phase III trial of ibrutinib and venetoclax; evaluation of ibrutinib/venetoclax in combination with an anti-CD20 antibody

DR LOVE: One final question related to this case. This lady now, what’s her current situation?

DR WIERDA: This patient has had about 18 months of combination therapy. She is in complete remission by virtue of having all of her lymph nodes less than 1.5 cm, and she is MRD negative in her bone marrow. Now, the trial design, as I mentioned, was 2 years of combination therapy, or 24 months, so she still is on combination therapy. And owing to the design of the clinical trial, what will likely happen for her is that at the end of the 24 months we will do a response assessment again. I expect for her to still be in complete remission. I expect for her still to be MRD negative. And we will be monitoring her after stopping therapy, serially, with blood MRD testing to evaluate for whether or not her disease comes back and what the timing is for that.

The challenge at this point for me in managing her is what to do with that information. Do we reinitiate treatment if she becomes MRD-positive? If we reinitiate treatment, does she go on ibrutinib monotherapy or do we try to get her back in an MRD-negative state with a combination or with venetoclax?

We don’t really know what the right approach is, and we’re having discussions now in our program about — we really would like, since these patients have participated in a clinical trial, we really would like to be relatively uniform and deliberate about what we do for them so that we can give further direction in follow-up, and so we’ll decide on an approach within our group and proceed in that regard.

DR LOVE: This strategy of combining a BTK inhibitor and venetoclax, I know it’s being looked at in a lot of different trials. Is it being looked at in a Phase III setting, and does it really need to be looked at in a Phase III setting?

DR WIERDA: It is being looked at in a Phase III clinical trial which is ibrutinib/venetoclax that’s ongoing in Europe. Yes, we will have Phase III data. I think it is important. And 1 of the discussions has been, we have CLL14 data. That’s venetoclax plus obinutuzumab. The complete remission rate is relatively high. The MRD-negative rate is relatively high, with that combination. People are asking, is there a difference between ibrutinib/venetoclax and outcomes versus venetoclax/obinutuzumab in the front-line setting? And we don’t have any data to answer that question.

Theoretically, I’m interested in the mechanism of how those drugs act. I’m interested in the mechanism of ibrutinib and the fact that ibrutinib interferes with the CLL interaction with the microenvironment. And I tend to think that mechanistically there’s a difference between those 2 regimens. But we need to generate data to support that, and we need to have the follow-up and some idea about long-term outcomes.

Our next clinical trial will be BTK inhibitor plus venetoclax, and patients will be randomized to receive an additional CD20 antibody or no CD20 antibody, with MRD as an endpoint. And with that, we will be able to determine whether or not the CD20 antibody is adding to the combination.

DR LOVE: That’s going to be a single-arm study?

DR WIERDA: No, it’s a randomized —

DR LOVE: Oh, randomized, wow.

DR WIERDA: Randomized Phase II based on MRD status.

DR LOVE: And just from MD Anderson? Or where are they coming from?

DR WIERDA: This is an MD Anderson trial, yes.

DR LOVE: Wow. Because I was going to say what about all 3 and — are there any other studies —

DR WIERDA: Yes.

DR LOVE: — looking at that — all 3?

DR WIERDA: The Ohio State group reported on all 3 together in a Phase II trial. I don’t know that there’s any randomized Phase III trials that are ongoing with all 3, but I anticipate. Others are looking at the 3-drug combination in Phase II studies. I anticipate that there may be a Phase III trial. We need a little bit more Phase II data before we consider that as an arm.

Potential clinical role of ibrutinib/venetoclax for patients with CLL

DR LOVE: It’s interesting, I was listening to you talk about this, and for some reason I flashed on this trial they did in breast cancer called the APT trial with HER2-positive disease, done by Dana-Farber, where they just did 1 arm. And what they showed was that the results were so good that you really couldn’t do any better by, for example, adding a more toxic chemotherapy, which is what it was looking at.

And I kind of wonder whether or not that kind of approach makes sense here. If you get people who are completely fine, MRD negative at 10 years, I mean, do you really need a Phase III trial. And what do you think about doing this right now outside a trial setting?

DR WIERDA: I mean, we’re getting spectacular results with ibrutinib/venetoclax. The problem and the challenge with doing it outside of a clinical trial is that you can’t usually get both drugs together. Insurance companies won’t pay for it.

We did, a few years ago, an analysis of cost of care looking at chemoimmunotherapy-based treatment like FCR versus BTK inhibitor-based therapy, and that was monotherapy. And we showed that there was a significant increase in the cost of care, and the cost of managing CLL in general, when we transitioned in an era of chemoimmunotherapy-based treatment to small-molecule inhibitor continuous and indefinite treatment.

We need to go back and do another analysis because we’re back at a discussion of can we give fixed duration with small-molecule inhibitor combination and manage disease that way and not have to have patients on continuous and indefinite treatment.

DR LOVE: Yes, I mean you would think that even just from a financial point of view in terms of these providers, you kind of look at the numbers. If they don’t get that combination, they’re going to get indefinite ibrutinib, so I guess over a couple years you know that it’s going to be more costly, at least in the short term, but —

DR WIERDA: Right.

DR LOVE: — we’ll see how it plays out.

DR WIERDA: Yes.

Case: A man in his late 50s with idiopathic thrombocytopenic purpura and del(11q) CLL with no IGHV mutation receives acalabrutinib after multiple lines of therapy, including venetoclax and ibrutinib

DR LOVE: I want to also ask you where we’re heading in — there’s so many things happening in CLL. And there was just a big press release that came out about a new trial. We haven’t seen the data yet, but it’s a Phase III trial, the ELEVATE-TN trial, that’s looking at acalabrutinib, the other BTK inhibitor now approved in mantle cell, here combined with obinutuzumab.

First of all, maybe we can get into 1 of your patients here, this 59-year-old man who actually was initially diagnosed in 2004. And he has a very interesting clinical history also. Maybe as a prelude to getting into this of other BTK inhibitors, we can hear about this patient.

DR WIERDA: Sure. This is a 59-year-old gentleman who I’ve been following since 2004. He initially presented with cytopenias and was diagnosed with ITP and concurrently diagnosed with his chronic lymphocytic leukemia at that time. Now, characterization of his CLL revealed that he had 11q deletion, and he had an unmutated V gene. And at the time, he needed treatment for his ITP, not so much for his CLL. He received rituximab, and that was the management for his ITP at the time. He actually received prednisone, and then rituximab, and received a total of 8 weekly doses of rituximab.

And he had a fair duration of control of his ITP, but his CLL subsequently progressed, and he needed treatment. He got 2 cycles of FCR as his first treatment. Now we know patients who have 11q deletion are very sensitive to alkylator agent-based therapy. They do very well with chemotherapy. They tend to go in remission. Their disease tends to relapse though, and they need to be treated repeatedly if we’re talking about chemoimmunotherapy-based treatment. Their overall survival is, believe it or not, similar to the other groups except for the 17p deletion, but they just tend to receive more treatment.

He did well with a couple cycles of FCR. He, in fact, went into a remission early, and his treatment was discontinued early, and he was monitored. And subsequently, a few years later, had recurrent ITP. For him, his disease activity, his CLL activity, correlated with his ITP activity. When his CLL started to become active again, his ITP would flare. He had a flare in his ITP and again got rituximab and ended up being refractory to CD20 antibody therapy and got a splenectomy. And then his CLL progressed subsequently, and he needed more treatment for his CLL.

He went on a clinical trial with lenalidomide and ofatumumab, and he received lenalidomide and ofatumumab on trial for several years, I think 3 years, 2 or 3 years. And then subsequently his ITP flared again, probably because he was becoming resistant. And he received more chemoimmunotherapy at that point. And that was in 2011. He received 6 cycles of FCR, which was re-treatment. He went in remission, but his remission was not a durable remission. It was about a year or so, and when he relapsed, he was treated on the initial Phase I clinical trial with venetoclax.

About a year after his FCR, he received venetoclax on a clinical trial. And he was on venetoclax for about 4 years, with good disease control. And that was up until about 2017. His disease eventually became resistant to venetoclax therapy. That was venetoclax monotherapy at the time. And upon progression he was placed on BTK inhibitor-based therapy.

And he’s an example of a patient who’s not a common patient these days. We’ve had ibrutinib available for a long time, so most patients, if they receive serial treatments, will receive ibrutinib first followed by venetoclax. But he’s an example of a patient, because he went on a clinical trial, who received venetoclax-based therapy first and then BTK inhibitor-based therapy with ibrutinib.

He went on ibrutinib monotherapy, not on a clinical trial, and he was on it for a while and had a nice response, not a complete response, but had a nice response, and started having arthralgias and myalgias, which we do see with ibrutinib. And sometimes we can dose adjust and reduce the dose and get patients on continued treatment and work through those symptoms. And other times we can get down to a low dose, and they still have these symptoms and problems, fatigue, arthralgias, myalgias, and we’re forced to either stop the treatment because the patient can’t really tolerate it long term or consider an alternative treatment.

Efficacy and side-effect profile of acalabrutinib versus ibrutinib

DR WIERDA: And in his case an alternative, a reasonable alternative, was acalabrutinib. Acalabrutinib is a second-generation BTK inhibitor. It works similar to ibrutinib in that is an irreversible inhibitor of BTK. It binds irreversibly to the cysteine 481 moiety of BTK and inhibits BTK in that way. It has a little bit different toxicity profile. It has a narrower kinome spectrum for inhibition, less off-target inhibition compared to ibrutinib. And that may be the reason why we see a little bit different toxicity profile.

We switched him over to acalabrutinib, and he is still not in complete remission. He still has a bit of a lymphocytosis. There’s still disease there. I would be very uncomfortable stopping all treatment and observing him. And so that was the reason why I switched him over to acalabrutinib, and he’s doing very well, with continued disease control and tolerating treatment very well on acalabrutinib.

As you mentioned, acalabrutinib is currently approved in the US for mantle cell. It’s not yet approved for CLL, but we’re anticipating soon because of the ASCEND trial results being available, which is a Phase III trial looking at acalabrutinib in the relapsed setting. We do anticipate that it will be approved soon in the relapsed setting. It is listed on the NCCN guidelines as an option for patients who are intolerant to ibrutinib because there’s clearly data, both in the relapsed setting and the front-line setting, showing activity with acalabrutinib.

I do use it as an alternative BTK inhibitor for patients. And the toxicity that we deal with predominantly is headache with acalabrutinib. It happens in a fair number of patients, but we usually can work through that with acetaminophen, and it subsequently will go away. He has not had any problems with arthralgias, myalgias and fatigue like he was with ibrutinib on acalabrutinib.

DR LOVE: That’s really interesting. There’s such a big difference in terms of those quality-of-life issues. Globally, at this point, what fraction of patients do you find some kind of either toxicity, a bleed or some kind of problem that will cause you to stop ibrutinib? Or maybe a quality-of-life one like these arthralgias?

DR WIERDA: Right, so if you look at the clinical trial data, now patients and physicians are more motivated to continue on treatment in the clinical trial setting. I think those data will show a lower proportion of patients coming off treatment in the clinical trial setting compared to in community practice. And it depends on when you look, so the longer patients stay on treatment the more likely they will be to come off treatment for some side effect or toxicity. In the front-line setting it’s roughly 30% of patients who come off of treatment because of a side effect or toxicity. It’s probably a similar number in the relapsed setting. People tend to be a little bit more motivated to stay on treatment if they’ve exhausted other options.

But a fair number of patients do come off treatment. In fact, more patients come off treatment with ibrutinib because of some side effect or toxicity versus those who come off because it’s not working any longer.

DR LOVE: I’m curious how many people you’ve actually used acalabrutinib in. Have you used it enough to get any kind of feel from your own practice in terms of comparative toxicity?

DR WIERDA: Sure. We have participated in the clinical trials with acalabrutinib, so I’ve treated a reasonably large number of patients with acalabrutinib. It does have a different toxicity profile. My own experience, my own personal experience, has been that it’s much less likely to need to dose adjust acalabrutinib for some side effect or toxicity than ibrutinib. Most of the patients will stay on the 100-mg BID dose of acalabrutinib without requirement for dose adjustment. And my own experience has been that a lower proportion of patients actually end up coming off acalabrutinib because of a side effect or toxicity.

We do see bleeding issues with acalabrutinib at low frequency. Also, A-fib has been reported with acalabrutinib. Those types of toxicities that are the low incidence type require a large number of patients to be treated and a reasonably large duration on treatment to get really a good idea of what the incidence is. And there’s a randomized trial that’s ongoing now of acala versus ibrutinib in the relapsed setting, where we’ll get some idea about the incidence of toxicities and the tolerability between those 2 treatment arms, in a randomized trial.

DR LOVE: I’m really curious about that trial. When do you think we might see some toxicity data? It seems like that ought to be able to come out fairly soon.

DR WIERDA: Yes, probably next year.

DR LOVE: Hmm.

DR WIERDA: 2020.

DR LOVE: That’ll be really interesting. Of course, the other issue is efficacy, and right now we just have indirect comparisons. Indirectly, do they look the same? Can you tease anything out?

DR WIERDA: I think for the most part, in my view of the data, they look similar. With acalabrutinib most of the patients have a response. Most of the responses are partial responses. There’s still residual disease in the blood, in the bone marrow, and so also with acalabrutinib we’re talking about continuous treatment.

Results of the Phase III ASCEND study of acalabrutinib alone versus investigator’s choice of idelalisib/rituximab or bendamustine/rituximab for relapsed/refractory CLL

DR LOVE: You mentioned this ASCEND trial that was presented. Can you talk about what they looked at there? What they saw? And again, indirectly, how that compares to what you see with ibrutinib?

DR WIERDA: With the ASCEND trial, that was a randomized Phase III trial in the relapsed setting of acalabrutinib monotherapy versus physician’s choice between bendamustine/rituximab or idelalisib/rituximab. Now most of the patients got idelalisib plus rituximab. A lower percentage got BR as their treatment. And on that trial there was clearly more toxicity associated with the idelalisib-based therapy. The toxicities were the ones that we usually see with idela — diarrhea, transaminitis.

The primary endpoint for that trial was progression-free survival, and there was clearly an improvement in progression-free survival for patients who went on and received acalabrutinib. No difference in overall survival, but the follow-up is relatively limited in that study. With longer follow-up, we may see some overall survival difference, but there’s clearly a difference in terms of progression-free survival with improved outcomes for patients who received acala-based treatment.

It’s hard to compare across Phase II trials/Phase III trials. It would be difficult for me to say outcomes of acala versus ibrutinib based on the data that’s seen in this study in the relapsed setting.

Ongoing Phase III ELEVATE-TN trial of acalabrutinib alone versus acalabrutinib/obinutuzumab versus chlorambucil/obinutuzumab for previously untreated CLL

DR LOVE: What about this other study? As it often happens in oncology, we first hear about it in a press release right after ASCO, this came out about this ELEVATE-TN trial, and this is first-line acalabrutinib. This is acalabrutinib/obinutuzumab, acalabrutinib alone, and then chlorambucil/obinutuzumab, and we’ll see when it’s presented, and we’ll kind of get more granularity to what’s going on. But it looks like kind of what you might expect, but also that the monotherapy arm was very effective and better than chemoimmunotherapy. Any thoughts about this? Obviously, we need to see the data, but from what you’ve heard how do you think it’s going to fit in the equation?

DR WIERDA: I think it’s going to lead to approval of acalabrutinib in the front-line setting. Ibrutinib was compared to chlorambucil, which I don’t think anybody would agree is a reasonable control arm these days. The bar is a little bit higher with this particular trial because they’re comparing it to chemoimmunotherapy. Nevertheless, as expected, the outcomes and the durability of responses and the progression-free survival is much better with a BTK inhibitor-based therapy than chemoimmunotherapy.

There are other trials that have looked at BTK inhibitor therapy, monotherapy, versus in combination with a CD20 antibody. We did a randomized trial at Anderson of ibrutinib plus or minus rituximab, and at ASH there was a trial that was presented in the front-line setting. This was the Alliance trial that evaluated ibrutinib versus ibrutinib plus rituximab versus BR. Now, none of those trials have shown an improvement in outcomes with the addition of a CD20 antibody to the BTK inhibitor-based therapy.

I’m expecting this trial to show the same thing, and my own personal opinion is that it’s probably because with all of these trials the BTK inhibitor-based therapy is continuous BTK inhibitor-based therapy. We’re not stopping the BTK inhibitor. That really drives the progression-free survival curve more so than addition of other things that are more cosmetic in terms of reduction of the white count, et cetera. You’re not looking at the depth of remission and how that correlates with outcomes in the setting of continuous BTK therapy.

I think if we were to do a trial with fixed-duration BTK inhibitor therapy, we could probably show an improvement with the addition of a CD20 antibody. But none of the trials were designed that way. We don’t recommend giving a CD20 antibody if you’re thinking about putting a patient on BTK inhibitor-based therapy which is continuous.

DR LOVE: It’ll be interesting if, as you hypothesize that acalabrutinib gets approved in the first-line setting, of course obviously it will depend a lot on exactly the approval and reimbursement, all this other stuff, but it’ll be interesting to see what people use outside of a trial setting. It was interesting, when we started to see this in mantle cell — we present these scenarios at our meetings, we ask investigators, et cetera. And of course when we presented people who had atrial fib or history of bleeding, for mantle cell, they immediately moved to acalabrutinib.

But the interesting thing was — even now, you see a lot of investigators moving to acalabrutinib in mantle cell just for a patient being older. Nothing, just being older. Do you see maybe that’s where things will head with CLL?

DR WIERDA: For sure. I mean, it may be driven more by what a physician’s experience has been, what their impression is of toxicities. We do know that with ibrutinib, for example, the older the patients are, the more likely they are to have a side effect or toxicity associated with ibrutinib therapy. Probably in the future, first choice of BTK inhibitor for front-line therapy, and for salvage therapy, will depend on physician experience and impression about the toxicity profile. These are treatments that are highly effective. We do want to be able to have the maximum benefit for our patients from whatever treatment that we choose for those patients.

Emerging data with next-generation, reversible Bruton tyrosine kinase inhibitors for CLL

DR LOVE: We talked a lot about ibrutinib and acalabrutinib. What other kinds of BTK inhibitors are being studied right now?

DR WIERDA: Right, acalabrutinib, ibrutinib and zanubrutinib, those are all irreversible inhibitors of BTK. They form a covalent bond with BTK and irreversibly inhibit it. One mechanism for resistance is mutation in the cysteine 481 that does not allow irreversible binding of those BTK inhibitors.

The next generation of inhibitors that we’re working on arereversibleinhibitors. They bind to that ATP pocket. They don’t require the cysteine 481 for binding to the pocket and therefore can potentially inhibit BTK even in cases that have a cysteine 481 mutation.

There’s a couple that are progressing in Phase I clinical trials that are of the reversible inhibitors. LOXO-305 is 1 of those. There’s a Phase I clinical trial with LOXO-305 that’s ongoing. SNS-032 is a second, or vecabrutinib is the name for this drug. Vecabrutinib is another compound that’s in Phase I development, and we’ll see more data.

BTK is clearly a viable target for CLL. And I think getting around the limitations of using an irreversible inhibitor with a reversible inhibitor may allow us to keep or stay on target longer, which I think is a very important therapeutic aspect for long-term management of the disease.

Mechanism of action, efficacy and tolerability of the recently FDA-approved antibody-drug conjugate moxetumomab pasudotox-tdfk for relapsed/refractory hairy cell leukemia

DR LOVE: I’ve got to take advantage of the fact that you’re the head of the NCCN committee on hairy cell leukemia. And everybody I ask about hairy cell doesn’t want to talk about it because they hardly see any patients. There’s a newly approved agent, moxetumomab, that always interests me, an antibody-drug conjugate, a very interesting drug. I don’t know how many people end up getting to use it. Can you just reflect a little bit back on hairy cell itself, and what are some of the key questions that have come out that you’ve been discussing in this committee, and particularly what your thoughts were about this new agent?

DR WIERDA: Right, so I think your impression is pretty consistent with a lot of the discussion. And that is patients do very well with our standard treatments. Most of them go into remission. Those remissions are lasting a long time. We’re still using purine analog monotherapy as first treatment for hairy cell. And we have other options. We have CD20 antibodies, which are used in the relapsed setting. One of the topics that has come up is, do we consider using purine analog with CD20 antibody as a first treatment? There are data that have looked at the response rate and improved outcomes. It’s hard to show improvement in outcomes when patients do so well with purine analog monotherapy.

We have options of purine analogs. If patients relapse, we can re-treat, depending on how long their remission, with a purine analog or an alternative purine analog and a CD20 antibody. We have vemurafenib, also, that has activity in relapsed hairy cell. That can be also combined with a CD20 antibody.

Now we have moxetumomab, which does have a significant toxicity profile. There are issues with hemolytic uremic syndrome, so it is challenging, and I personally have not used it. It’s recently been approved. But there have been reasonable challenges reported with it, and toxicities reported with it, and I don’t think there’s been a lot of usage with it, or for it. But nevertheless it is an option for patients who have multiply relapsed hairy cell.

DR LOVE: I’m just always interested when I hear about a new antibody-drug conjugate, because you hear about so many, there’s like 3 of them in breast cancer, a bunch of them out there right now. Always interesting to me some of the side effects that you see. And this one, as you mention, hemolytic uremic syndrome. I’m not sure I’ve heard about that before. This is like conjugated to a pseudomonas thing?

DR WIERDA: Right. It’s a pseudomonas toxin that shuts down protein synthesis. And there’s a fair amount of hepatotoxicity that you can see with this agent.

There was another agent that was also approved previously, and it was used. We tested it in CLL many years ago, didn’t have activity in CLL, and it’s used for T-cell disease. It’s an IL-2 conjugate that also had hepatotoxicity associated with it, and it wasn’t a monoclonal antibody-drug conjugate, it was a cytokine conjugate, but had toxicities similar to what we see with moxetumomab.

Case: A woman in her early 60s with del(17p) CLL and no IGHV mutation receives venetoclax and obinutuzumab as first-line therapy

DR LOVE: Let’s just finish out briefly with 1 more case. Why don’t we hear about your 61-year-old lady who was diagnosed in 2014?

DR WIERDA: The 61-year-old patient, she also had high-risk features. She was diagnosed in 2014, and at her diagnosis was noted to have 17p deletion. She also had an unmutated V gene. We have routinely tested for ZAP70, and it does correlate with mutation status, but we found it to be less useful. I probably would not recommend that for routine evaluation. Nevertheless, she was ZAP70 positive, and she was initially monitored until she progressed almost a year later.

And when she progressed, she went on a clinical trial, a first-line clinical trial, with venetoclax plus obinutuzumab. This is a trial that was an initial analysis generating an initial safety data set in parallel with the CLL14 trial. She went on venetoclax/obinutuzumab. And she went into a remission with that. That was a fixed-duration treatment, so she stopped her venetoclax, I believe it was about a year after she had started treatment.

And although she was in a complete remission and was MRD negative at the end of treatment, she subsequently, about 3 years later, had progression of her disease. And at that time, she needed salvage therapy and was placed on ibrutinib. She had 17p deletion at relapse. She had high-risk features. And her response to ibrutinib monotherapy was relatively limited.

She achieved a partial remission. She had about a year of disease control on ibrutinib, and subsequently her disease progressed in the form of a progressive cervical node, or nodal group.

When she progressed after the ibrutinib, she was evaluated for mutations in BTK and PLCG2 and did not have those mutations. She also had a PET/CT to make sure she didn’t have a Richter’s transformation when she progressed. And, in fact, I think she also had a lymph node biopsy, even though she didn’t have a high SUV. She did not have Richter’s transformation, and she went on a clinical trial recently with CD19 CAR T-cell therapy with JCAR017.

And she’s achieved a partial remission with that and is now continuing on observation and close monitoring on continued BTK inhibitor-based therapy.

Activity and safety profile of chimeric antigen receptor (CAR) T-cell therapy for CLL

DR LOVE: I’m curious what happened when she got the CAR-T therapy in terms of cytokine release, neurologic issues, et cetera.

DR WIERDA: Right. For her, particularly, she did not have cytokine release. She did not have neurotoxicity. She’s on the JCAR017 trial. That trial initially was with CAR T by itself. The patients get lymphodepletion. They get CAR T. She actually went on the arm of patients who get CAR T in the setting of ibrutinib. The other groups have reported a decrease in the incidence of CRS when you combine ibrutinib with the CAR T. And there’s theoretic reasons why you may see increased activity. CAR-T therapy for CLL has been less impressive than for DLBCL in terms of complete remission rate and long-term outcomes.

She was treated on a clinical trial and received ibrutinib with the CAR T. She didn’t have a large bulk of disease when she got her CAR T. She just had her cervical nodal disease and some, about 50%, involvement in her bone marrow was CLL. And she did not have significant CRS or neurotoxicity on the study. She was a little bit concerned because she wanted to see some toxicity because they’re anticipating that, and that correlating with efficacy. But she did get a response. Her bone marrow was improved. She was not MRD negative at her last follow-up, but we’re continuing to follow up with her. And, as I mentioned, she remains on ibrutinib on that study.

DR LOVE: It’s interesting, I’d heard about the idea of combining various things with CAR T, including ibrutinib, but I hadn’t heard about this thing about the idea of less CRS. Is there any reason to think that it’d be less antitumor effect? And what do you understand? Ibrutinib’s now used for GVHD. What do you understand about the immunologic effect of BTK inhibitors?

DR WIERDA: Yes, we don’t have a good understanding. We still see infections among patients who are on ibrutinib. It is not immune restorative, or does not immune reconstitute patients. Patients still have hypogammaglobulinemia on ibrutinib. There is modulation of the immune system and immune function with ibrutinib. I don’t have a good understanding of the details of what that is. I don’t know that anybody does. It is used for chronic GVHD, and that’s based on its immune modulatory effects.

At ASH, this last past ASH, there were 2 groups that reported on, and they did a historic comparison of a cohort of patients who received CAR T versus CAR T with ibrutinib. That was the UPenn group, and Fred Hutch Seattle group. And in their analysis, it does not look like there’s worse, and perhaps there’s better outcomes in terms of response with the addition of the ibrutinib. And there does tend to be a lower incidence of cytokine release and severity of cytokine release when you add the ibrutinib for some unknown, unclear reason.

DR LOVE: You mentioned about the CAR T in CLL not being as effective, but, and I was kind of curious that you don’t see more about CAR T in CLL because I think that’s part of the beginning. You mentioned Penn, and they initially reported a couple CLL patients, I think, right in the beginning. And I haven’t been clear whether it’s lack of efficacy or the fact that there aren’t enough patients who like get to that point with CLL. I mean, do you have patients in your practice die of CLL that maybe could benefit from CAR T?

DR WIERDA: We do. They’re not very common. We have more patients dying of Richter’s transformation —

DR LOVE: Right.

DR WIERDA: — so there’s definitely a need in Richter’s transformation. The number of patients available for those types of trials is limited.

We have other very exciting clinical trial options for patients with relapsed and refractory disease. For example, the reversible BTK inhibitors. The numbers of patients are limited. If you look at the data, the Phase I/Phase II data with CAR T in CLL, the long-term progression-free survival is roughly 20%, 25%. That’s lower than it is for DLBCL, which is 40%, 50%. And it’s harder to appreciate a plateau on a curve if you’re talking about a 20%, 25% long-term progression-free survival.

Challenges in the clinical management of CLL

DR LOVE: I sit here like an amateur scientist trying to figure out what all that you’re doing there in terms of some of these results, and where, maybe, CAR T would fit in in the future in terms of CLL. But I was thinking about the fact, and it just seems kind of weird, myeloma now, CAR T, even though it’s a completely different target, et cetera, maybe not as exciting. And I was wondering if what we’re kind of seeing is like coalescence around the biology. It’s not just about destroying the cells. You have diffuse large B-cell, which kind of has a biology of acute cure as opposed to something like myeloma and CLL, with more chronic disease. Does that make any sense to you?

DR WIERDA: Yes. It does, and I think when you’re asking the question I’m reflecting and trying to think about what are the big topics in CLL? We have very good, effective small molecule inhibitor-based therapy. We still struggle with 2 topics in CLL. We struggle with Richter’s transformation. It’s still happening. It’s still happening even with the small molecule inhibitor-based therapy. I think it’s probably related to the genomic instability in some cases of CLL, where you get events that convert the disease to a much more aggressive form, and that’s what causes a Richter’s transformation.

We see Richter’s transformation. We still don’t have very good treatments for Richter’s transformation. Patients are still going to transplant, if we can get them there, who have Richter’s transformation.

The other area that we struggle with that we have a very large knowledge gap in is the immune system and immune function in patients with CLL. The disease itself does affect immune function and the immune system. We don’t have a good understanding of how that happens or how it does that. And because of that, patients are still at risk for infections. We still see a fair amount of infections in patients who are on small molecule inhibitor-based therapy.

Infection is still a risk. We still see hypogammaglobulinemia.

Patients who are in good, deep remissions are still getting IVIG because they’re hypogammaglobulinemic. We still see second malignancies developing at a higher incidence in patients who have CLL, even those who are on small molecule inhibitors that are achieving a deep remission.

The immune function and the immune status is really the next big gap and area that we need to focus our attention on. And we’re going to see this transition, I think, of patient survival not necessarily being shortened by the disease per se, or resistant disease, but more so by development of infections and transformation events.

Emerging data and recent advances in the management of CLL

DR MATO: ASH and ASCO this year really have been practice changing for oncologists. We had the great fortune at ASH to have several studies presented that really provide a thematic change for patients with CLL.

There were the data presented from the ECOG 1912, the Alliance trial, the iLLUMINATE trial and then updated data from the MURANO trial. And the big picture theme is that the days of chemotherapy or chemoimmunotherapy for patients with CLL are really coming to an end, with the exception of very, very specific patient groups.

In the ECOG trial we saw FCR, which had been a great standard of care for patients, compared to ibrutinib and rituximab. And ibrutinib and rituximab was better in terms of the primary endpoint for progression-free survival.

The Alliance trial was a similar question but for older patients and there, ibrutinib with or without rituximab was compared to bendamustine and rituximab. And again, same primary endpoint was met for progression-free survival.

We saw the CLL11 regimen, which was obinutuzumab plus chlorambucil challenged by the combination of ibrutinib plus obinutuzumab, and there again a primary endpoint of progression-free survival was met.

And then we saw updated data from the MURANO trial, which was venetoclax plus rituximab compared to bendamustine and rituximab in the relapsed/refractory setting. Update PFS data, OS data, depth of response data, but I think more importantly, that was the first novel agent combination that allowed for a fixed duration for patients.

All of the data that I mentioned with ibrutinib, either alone or with rituximab or with obinutuzumab as continuous therapy, which is something that patients do question at times. The venetoclax therapy was a fixed duration of 24 months and then all patients stopped. And we got a window into what happens the first year after discontinuation where we saw about a 13% rate of progression of patients, so sort of a modest rate of progression off therapy with the hope and expectation that those patients could be rechallenged with venetoclax when they develop symptomatic CLL that warrants an intervention.

That was ASH, and that’s a lot of information for just 1 meeting.

Then at the ASCO meeting we saw the CLL14 presented, which was the combination of venetoclax plus obinutuzumab. And there, the comparison was the CLL11 regimen, a modified CLL11 regimen of obinutuzumab plus chlorambucil — randomized trial, older patients, a lot of comorbidities. And there, the primary endpoint was met for progression-free survival. But that’s the second trial that showed a fixed duration of novel agent chemotherapy for patients. There, everybody got treated with 1-year’s worth of therapy and then discontinued.

We’re moving towards combinations where we’re improving the CR rate, the MRD undetectable rate, and because of that, patients are able to stop therapies and have these breaks that are hopefully lasting several years before we even need to rethink about rechallenging patients.

Perspective on the role of MRD assessment in therapeutic decision-making

DR LOVE: It’s interesting, in listening to investigators discuss various diseases, we, as a CME group, often generate algorithms kind of based on what we hear. And we had this algorithm we’ve been developing the last year based on p53, del(17p) and IgVH mutation, and at ASH it just totally blew up. It was just like things completely changed. And then as you say, they changed even more at ASCO. And for somebody in general oncology practice who’s also trying to keep up with which PD-L1 assay to do in bladder cancer, whatever, it’s not very easy to sort out.

Let me just ask you some macro questions with this huge amount of data coming in. The first thing is, you mentioned the idea of this short-term treatment and often that is integrated with MRD measurement. Can you talk a little bit more about that strategy and whether you think it would be reasonable to do right now outside a trial setting in community practice?

DR MATO: Making treatment decisions based on MRD is a goal and it’s not really ready for community or academic practice at this point.

The 2 trials that I mentioned with fixed duration, the MURANO trial and the CLL14, were really one-size-fits-all for all patients — everybody either got 24-months’ worth of therapy or 12-months’ worth of therapy and then stopped.

There is no decision point yet integrated into novel agent-based therapy that’s based on an MRD endpoint.

These trials have performed MRD assessments in the blood or in the bone marrow, either by PCR or by sequencing or by flow cytometry and they are very happy to report that there are a high proportion of patients who are MRD undetectable exceeding 60 or 70%. But if you actually look at the trial design for practical purposes, everybody gets treated exactly the same regardless of their MRD results. If you’re getting venetoclax in the relapsed/refractory setting, you get ven plus rituximab 24 months and stop.

Probably the patients who are MRD undetectable at the end of therapy do better, but it’s still not a decision point. And the same is true with the CLL14 with the 12 months of obina plus ven and then stop.

And I really feel the future is going to be we shouldn’t do one-size-fits-all targeted agents for patients, and we should be making decisions based on biology, and 1 of those endpoints should be assessment of MRD. But we don’t even have studies yet available that would support that decision-making.

Duration of therapy for patients with CLL; integration of venetoclax into the treatment algorithm

DR LOVE: Your point’s well taken.

I guess what I should say then is, what about the strategy of using short-term treatment in general outside a clinical trial?

DR MATO: I think clinical practice is ready for that, absolutely. Venetoclax, and really the only strategy we have right now with a novel agent is venetoclax — that was approved initially as a continuous agent, relapsed/refractory setting, for del(17p) patients, but that’s been expanded now. And so both in the front-line and relapsed/refractory setting, there is really a lot of experience both at academic centers and emerging in community centers to use venetoclax for a fixed duration and then stop.

I think right now across the US and certainly in my practice we’re using venetoclax that way — both front-line and relapsed/refractory. We’re there already.

DR LOVE: I could imagine in a patient who’s tolerating, let’s say, novel therapy well, that might be a difficult decision to stop therapy. Would you advise against looking at MRD?

DR MATO: I wouldn’t advise against it, but I would highlight that it’s still a research question. And to be completely fair, these approvals are so relatively new that even in my practice we don’t have a lot of patients receiving standard of care, either ven/rituximab or ven/obina who’ve gotten to 24 or 12 months where we’ve had to really face that question, and we’re talking about an approval for ven in the front-line setting that’s about 3 weeks old.

There really shouldn’t be a lot of patients in practice that are receiving that combination where that decision point has been met yet. But I agree, if I have a patient at 12 months who has MRD-persistent disease or -detectable disease, it’s going to be a conversation that will be a prolonged conversation and we don’t have a lot of data to help support the decision. I think it’s going to be an important question in the near future.

DR LOVE: Yes. I mean it might be fine to stop therapy even in a patient who’s MRD positive. But it kind of reminds me of the conversations I had with myeloma people, you talk about using MRD to decide about transplant and they go “Oh, well the data’s not there.” But, on the other hand, from, kind of, a clinical point of view it sort of makes sense. But I guess that’s going to be for the future.

DR MATO: Yes. I can tell you we’re designing about 5 trials right now at MSK, and decision-making is going to be based on MRD. It’s very relevant right now from a research perspective.

Available data with the addition of rituximab or obinutuzumab to novel therapies

DR LOVE: Another macro question I have, seeing all these data come out, is the issue of anti-CD20 therapy plus novel therapy plus ibrutinib, plus venetoclax. And I know you’ve written about this, what evidence do we have, whether it’s obinutuzumab or rituximab that these agents in the long term — because we could use them on relapse, too — in the long term it’s better to give with these novel agents?

DR MATO: I think that’s probably 1 of the most important questions right now in CLL. And I think 1 of the major, major limiting factors of clinical trials to date is the fact that we have these novel agents that were approved as monotherapies, but very infrequently do the trials, looking at combinations, include either ibrutinib or venetoclax as a monotherapy to really guide us. What’s the incremental benefit of adding other agents to that drug which is already great and a standard of care?

And as you know, a couple of examples I would highlight from ASH last year and the year before, the MD Anderson group presented data in the relapsed/refractory setting of ibrutinib plus/minus rituximab. Before the trial was conducted, everybody would have said rituximab is going to add to depth of response. They’ll be more durable, they’ll be deeper and the PFS will be better. But there was absolutely no difference in PFS overall survival. Rituximab added nothing in the relapsed/refractory setting.

And then we have the Alliance data that were presented at this ASH meeting looking at ibrutinib plus/minus rituximab in the front-line setting versus BR and there was absolutely no benefit to adding rituximab to ibrutinib.

I think for rituximab plus ibrutinib we have an answer: 2 randomized trials, rituximabadds nothing to ibrutinib.

The question of obinutuzumab is a little bit more open-ended, but of course it’s not answered. The iLLUMINATE trial was ibrutinib plus obinutuzumab versus obina plus chlorambucil. I would have argued strongly that ibrutinib should have been included as a monotherapy control, a 3-arm trial, and it wasn’t conducted that way. We don’t know if obina adds to ibrutinib. I think most people in practice are extrapolating from the rituximab experience.

There is a trial that’s very interesting right now that will be reported I think within the next year or so, which is the BTK inhibitor acalabrutinib versus acalabrutinib plus obinutuzumab versus obinutuzumab plus chlorambucil. That’s a front-line trial. And there, fortunately, we have the glycoengineered anti-CD20 with or without the novel agent. So that will probably help settle the question for obina with a BTK inhibitor.

I think venetoclax is even more unanswered because we have the ven data from the relapsed/refractory setting as a monotherapy. Looks great. But the MURANO trial did not include a ven mono as a control. And the CLL14 did not included a ven mono as a control. We really don’t know the incremental benefit, if there is one, to adding a CD20 to venetoclax.

About 20 centers from around the world got together, and we contributed our data for ven plus/minus a CD20 as one of these retrospective, real-world studies, where we wanted to try to answer the question that wasn’t going to be answered in the context of a trial. And we published those data in Blood Advances, and we didn’t see any benefit to adding a CD20 to venetoclax. Which I really think speaks to the value of those types of studies in trying to answer questions that may not easily be answered in the context of clinical research.

Selection of patients with CLL for treatment with FCR (fludarabine/cyclophosphamide/rituximab)

DR LOVE: One subset that’s been out there for a while and got shaken up a lot at ASH is the younger patient who could potentially tolerate FCR with IgVH mutated, p53/del(17p)-negative disease. I still hear investigators saying FCR for the idea of short-term treatment/long-term benefit. Where are you on that question today?

DR MATO: I do still think there is a role for FCR in that very, very highly selected patient population that you already stated, the TP53 intact, IgVH mutated, younger — and I would define “younger” as 65 or younger based on the clinical trials’ experience. It’s hard to argue with 2-decades’ worth of long-term follow-up data from various centers starting with MD Anderson, but also looking at data from Germany and from Italy that supports the point that there probably is a proportion of patients in that subgroup who receive FCR and may be cured of their disease. If not cured, treated to a point where the remission is so deep that it will not likely return during the course of their lifetime.

And it is really interesting, but if you dissect the data for CLL14 from the ECOG trial, from the Alliance trial, and you look specifically at the subgroup of patients who are IgHV mutated, there’s really no difference in outcomes; the hazard ratios are not significant.

I think it’s still an unanswered question. And probably what we need to do moving forward, is trials really need to be designed looking at patients stratified by IgHV status. Unmutated patients probably warrant a different trial design than mutated patients.

I recently saw a patient in the office who’s young and fit and who meets those characteristics perfectly, and part of our conversation was that there is still a role for FCR for that patient and it is something that needs to be considered.

Novel combination approaches to limiting the duration of therapy for patients with CLL

DR LOVE: I guess 1 issue might be this idea of short-term novel agent therapy or combinations, maybe that might offer an FCR-like short-term model.

DR MATO: I think so, but again the same point as earlier with some of the other trials is that the way these combination studies are being designed, they are demonstrating high rates of response and undetectable disease, but there’s definitely a trade-off.

And when you look at the AE data for a combination like ibrutinib and venetoclax, it’s certainly much higher than either agent alone. And I think that the question that will always remain outstanding in my mind — and just using that as an example — is do we use all of our best agents together or is there really a value in giving these agents in sequence with one another?

And you can look at the data from the RESONATE-2 trial, which was the front-line ibrutinib trial, we’re at 5+ years and we still haven’t reached the median PFS.

You could look at the MURANO or the venetoclax data, which is available following ibrutinib or idelalisib, you’re looking at a minimum median PFS of 24.5 months. If you start to argue, 50, 60 median PFS for ibrutinib, 3 years with venetoclax, how do you come up with a combination that starts exceeding that when you start thinking about the PFS in sequence?

I think the combinations may offer a window into short duration of therapy, but we also really don’t know a lot about the side effects. And the big question in my mind is, when you give drugs like ibrutinib, venetoclax and obinutuzumab together, what does resistance look like in that patient if and when they finally progress? Is it driven by BTK or Bcl-2? Are they CD20 refractory?

We barely understand the biology to resistance to any of these agents by themselves.

I think it’s unchartered waters and regardless of how many of these studies are published and how spectacular the data look. Until we have some more randomized data or sequencing questions answered, I’m a little bit hesitant to jump on that bandwagon.

Spectrum and incidence of toxicities with ibrutinib/venetoclax compared to either agent alone

DR LOVE: You said something that I don’t know that I’ve heard before, which is that when you combine a BTK inhibitor and venetoclax or ibrutinib and venetoclax you have significant increase in AEs?

DR MATO: Yes. If you look at the data — there’s, most recently, data published in New England Journal of Medicine looking at ibrutinib plus venetoclax — certainly more AEs and different AEs than either agent given alone. Now you could argue whether or not those AEs are additive or synergistic, but there’s a higher proportion of — I think this is true in all of oncology and not related to CLL specifically, but the more drugs you put together, the more additive the toxicities are for patients.

DR LOVE: I would assume these are BTK-type toxicities because — I mean you tell me, what are the toxicities of venetoclax once you get people through TLS?

DR MATO: Hematologic toxicities.

DR LOVE: Hematologic.

DR MATO: You start —

DR LOVE: You see more cytopenias, for example?

DR MATO: Yes. Exactly. You see neutropenia, thrombocytopenia. And what’s interesting to me, and this is still unanswered from the combination questions, if you really dissect the data for the combinations, like the one I just mentioned, there is a very significant proportion of patients, probably still a minority but bordering on a majority, that are requiring dose reductions of — of 1 or both agents because of the fact that there are hematologic toxicities, for example, or arthralgias, for example, or A-fib, for example.

Those things really do need to be considered: Are 2 drugs at lower doses better than 1 drug at the FDA-approved dose? Still don’t know that answer.

DR LOVE: But I mean, do you think that the BTK-type toxicities, like atrial fibrillation or arthralgias, are greater if you add in venetoclax?

DR MATO: I don’t know that for sure, although you might argue that A-fib could be more exacerbated if you have — for example, exacerbation of anemia with another drug that has myelosuppression and it’s more stress on the heart.

We don’t know that for sure, but certainly if you look at all-grade AEs or Grade 3/4 AEs, I do think, with the combinations — the novel, novel doubles, or the novel, novel plus anti-CD20 triples — that there is a higher rate of toxicity that definitely needs to be presented to patients as part of informed consent.

Therapeutic options for patients with CLL in the first-line setting

DR LOVE: I want to get into some of your cases, but first ask you a real simple question, which is, what’s first-line therapy of CLL nowadays?

DR MATO: There’s not 1 right answer to that question. I think what you alluded to earlier about performing a prognostic evaluation is really key. There’s a lot of different prognostic markers that one could perform, but it probably really boils down to 3 or 4, and that’s checking IgVH status, FISH, specifically for deletion 17p — the others don’t matter as much to me — next-generation sequencing, specifically for a TP53 mutation. And that information together really can help to guide therapy.

If a patient is a perfect candidate for FCR, like we talked about earlier, it’s still part of the conversation. Otherwise, things have gotten much simpler for patients and oncologists at this point in time. It really boils down to novel agent-based therapy with the 2 or 3 choices available — ibrutinib, ibrutinib plus obinutuzumab, or venetoclax plus obinutuzumab.

Of course, we don’t have head-to-head comparative data of ibrutinib plus ven, so the conversation is really a long one discussing the advantages and disadvantages of ibrutinib and venetoclax. And I could get into that because it is something that we talk about every day with patients.

With ibrutinib, it’s a continuous therapy, so that may be 1 disadvantage that patients may consider. But on the other hand, we have 5+ years follow-up as a first therapy, so that’s reassuring for patients. And we have sequencing data available. There are prospective data which support the use of venetoclax following discontinuation of ibrutinib. You’re looking at a 65% to 70% overall response rate, a median PFS of 24 months.

Safety profile and quality of life with venetoclax versus ibrutinib

DR MATO: A disadvantage of ibrutinib is it does have certain toxicities that need to be addressed — rash, arthralgia, bleeding, bruising, atrial fibrillation and infection — those are some of the ones that we think about.

Venetoclax, it’s a little bit of a different conversation. It’s a time-limited therapy but of course, as a first therapy, it’s not a monotherapy — it’s given with an infusion, obinutuzumab. You have to commit to that 6 months’ worth of infusion.

The ramp-up can be cumbersome at times, depending on your TLS risk. And so you might be in the office a fair amount for the first 5 weeks of therapy or even hospitalized.

The AE profile is different, but it’s not insignificant. There is a risk of TLS, which is very low if you follow the rules, but also hematologic toxicities, some minor GI toxicity. Probably 1 of the biggest limiting factors at this point is we don’t really know which therapies work best after venetoclax. It’s not to say ibrutinib wouldn’t work; it’s just that I couldn’t cite a study that gives us prospective data to support that. There’s like a case series from Australia with 6 or 7 patients. There is a few from the US that we reported.

But really not a lot of robust prospective data to support that sequencing strategy.

It’s one of these situations where for patients and oncologists, we want to have this Level 1 evidence to help choose 1 therapy versus another. And the truth of the matter is that they’re both great therapies and we just have to live with the limitations of the clinical trials.

DR LOVE: So if a patient says to you, just from a quality-of-life point of view, I understand the issues about efficacy might be a little complicated, but in terms of how a patient’s going to feel, how would you compare life on ibrutinib to life on venetoclax?

DR MATO: I have had to discontinue both drugs due to adverse event, but when they work well, and I would say the answer to most patients is, in the vast majority of cases, either ibrutinib or venetoclax, they have a great quality of life, certainly relative to chemotherapy days, that we try to take it case-by-case basis. If I have a patient who has really significant, poorly controlled hypertension, atrial fibrillation, they’re on blood thinners that may not be the best patient for me to start ibrutinib.

I have a patient who I mentioned early to you has von Willebrand disease, has a bleeding diathesis already, probably not going to start ibrutinib.

If I have a patient who’s already starting off with significant neutropenia related to their CLL, then I may not think venetoclax is the best therapy for that patient, particularly short term, from a risk of infection. I think the answer is not one over the other, but really knowing your patient, knowing the drugs, and also, knowing yourself. If you have much more experience using ibrutinib in managing their AEs, it’s probably the better drug. The same is also true for venetoclax. If your office is not well equipped to do a ramp up, then it’s probably not the best choice for a patient.

You have to really consider all 3 of those factors.

Frequency of and reasons for discontinuation of therapy with ibrutinib

DR LOVE: When you start out with a patient who doesn’t have any significant comorbidities, in your mind what are you thinking over time is the likelihood that they’re going to have to stop ibrutinib over 1 year, 3 years, 5 years because of some type of adverse problem?

DR MATO: Yes. We’ve reported these data from the real-world studies and the clinical trials are largely with long-term follow-up confirming approximately, I would say, one fifth of patients would have to stop a drug due to an adverse event over some period of time, let’s say, over the first 5 years’ worth of therapy.

It’s the most common reason for dose discontinuation and it’s a little bit different when you’re talking about front-line or relapsed/refractory setting. I would say either 10 or 20% of patients will discontinue due to an adverse event.

Now whether or not that adverse event could be managed medically I think is another question. There are certain cases where an oncologist may have A-fib that’s relatively well controlled but not feel comfortable to continue the drug.

I’ve actually found that working with cardiologists, internists, cardio-oncologists really closely, there are very few ibrutinib-related events that absolutely mandate discontinuation of the drug. It’s really a question of what your resources are or at your center, do you have partnerships with other specialties where you feel comfortable to manage through those events.

DR LOVE: That’s interesting because when you say 10% or 20%, that kind of sounds low compared to other estimates. But now are you talking about in your hands or out in the community?

DR MATO: I’m talking about in the community. And the reason being is that some of the literature that we’ve published has been misquoted. We’ve always talked about ibrutinib and the most common reason for discontinuation is adverse event, the number that we’ve published is 50% of discontinuations, but oftentimes that 50% gets quoted. It’s 50% of the discontinuation rate.

In the relapsed/refractory setting, we quoted the discontinuation rate was about 40%, but that included progression — and transformation, financial issues.

In the front-line setting, we reported 24% discontinuation rate, so half of that would be due to AEs, so that brings you to around 12.5%.

Left atrial abnormality as a predictor of ibrutinib-associated atrial fibrillation in patients with CLL

DR LOVE: You were talking about atrial fibrillation. I’ve got to ask you about this paper in a journal that I don’t usually read, Cancer Biology & Therapy, on “left atrial abnormality as a predictor of ibrutinib atrial fibrillation.” Never heard of that.

DR MATO: That was really a project I enjoyed doing. I did that with Dr Joe Carver who is the head of cardio-oncology at University of Pennsylvania, and that was an attempt to try to understand which of our patients would develop atrial fibrillation prior to the start of ibrutinib. And we had this hypothesis that if patients had any abnormality in conduction within the atria or the size of the atria, those patients would be at highest risk.

And so I worked with Dr Carver to develop 3 different criteria looking at conduction delays or P mitrale or other abnormalities that you could see in the atria that might predict which patients would develop A-fib later on. And it was really simple — you could use the ECG very reproducible criteria. Any internist or cardiologist could follow those guidance. And the odds ratio was somewhere between 2 and 3 that those patients would be at higher risk.

I wouldn’t say if you had those abnormalities that you shouldn’t use the drug because it’s still a relatively low risk, but I would say if there’s something wrong with the atria on an ECG it’s probably worth getting an echo. It’s worth paying more attention to that patient, looking for symptoms, palpitations, anything that might be suggestive of A-fib. Because if you can catch it early, you can manage these patients with rate control, plus/minus an aspirin or anticoagulation. And so we presented that 2 years ago now at the IWCLL meeting, which was in New York City, and we published those data in Cancer Biology & Therapy, which is a very neat journal where they allow bench-to-bedside or bedside-to-bench articles to be presented.

DR LOVE: Yes, I’ve got to check that out.

Are you actually doing that in your practice? Have you incorporated that?

DR MATO: It’s not a formal incorporation, but we do look at patients’ ECGs to see whether or not there’s anything that might raise a concern. And certainly at Penn, if I had any patient like that, I would have immediately recommended they see Dr Carver. The same is true at MSK with our cardio-oncology group.

DR LOVE: Interesting.

Real-world outcomes and management strategies for patients with venetoclax-treated CLL in the United States

DR LOVE: Another paper I want to ask you about that you did — I’m always fascinated by real-world outcomes work and you’ve done a lot of it — and in particular I was curious about this paper you have looking at real-world outcomes related to venetoclax. I’ve been curious about that in terms of what people are actually doing. What did you find there?

DR MATO: That was a paper that we published in Haematologica last year where we were gathering data from centers across the world, a huge amount of data came from US, but also a large amount came from the UK, where we wanted to just look at everyone’s practice for use of venetoclax and try to understand how well was the drug performing? What were the adverse events? What was the risk of TLS? Were people following the FDA label? Were they deviating from it? It really gives you a window into how these drugs perform out of the context of clinical research.

For anybody who’s conducted a clinical trial, this is really an elite group of patients. They’re usually very fit. They have the best organ function. Their creatinine clearances are over a certain threshold. This was a chance for us to get a first look at ven post approval, and actually the drug performed quite well. This was one of the real-world experiences where I felt the data pretty closely matched the data from clinical trials.

There certainly were probably a slightly higher rate of AEs that were reported, Grade 3/4 toxicities. TLS seemed to be a little bit more prevalent than one might have expected from the clinical trials. But, also, keep in mind it was an older patient population, creatinine clearances were likely decreased. But overall we had a pretty favorable impression of the ven experience. People were very closely following the label, actually to an extreme. There were more patients hospitalized for TLS ramp-up for monitoring and prophylaxis than even would have been required per label.

It was interesting to get that look. And we’ve subsequently published another paper in CCR this year where we were trying to do a little bit of modeling of TLS risk but also get another look a year later to see if things have changed significantly.

Experience conducting real-world outcome studies

DR LOVE: You did the study or how did you actually — I’m just kind of curious how you did this.

DR MATO: All of the real-world studies that we’ve published have been unfunded trials where we’ve really come up with these questions that are not only relevant in our practice but relevant to our patients. And I think the proof of the fact that they’re relevant is the fact that we email colleagues or reach out to colleagues from different centers around the world and say, “Hey, would you be willing to participate?”

The answer has always unanimously been “This is really worthwhile. We want to know the same thing.” But in any practice, even MSK or Penn or anywhere where you work, there’s probably not enough patients at 1 center to answer the question.

We’ve worked really hard to put together this informal consortium of centers worldwide where every time we have a relevant question we get together and we pool our data, obviously through having IRB-approved retrospective protocols for this type of work, combine, analyze and then as a group decide what are the relevant findings and then present those at meetings like ASH or ASCO or IWCLL and present the papers.

I think probably over the last 3 or 4 years we’ve had somewhere between 6 and 8 real-world papers that were published. As a result, we’re working on 1 now, focused on venetoclax, where we’ve had over 40 centers worldwide — from as far away as Russia — send us emails requesting to participate because they really want to share their data, participate in the experience, and I think everybody recognizes that there are just not going to be certain clinical trials conducted. And really the only way for us to answer questions for our patients specifically is to gather our information. It’s better to collaborate and share data than it is to be isolated in a silo where no one’s working together.

And actually 1 interesting thing that’s come out of this is that we’ve identified questions from our retrospective studies that we think are relevant for clinical trials and we’ve actually gone on to then conduct the clinical trials.

We developed a trial looking at a PI3K inhibitor, umbralisib, specifically for ibrutinib- or idelalisib-intolerant patients to see whether or not we could class switch and maintain response. That trial completely was born from the real-world trial that we published in 2015 in Blood, where we were looking at class switching between ibrutinib and idelalisib. This informal real-world group has now actually turned into a consortium where we’re conducting clinical trials together. And the questions are all coming from the retrospective reviews.

Role of chemoimmunotherapy in the management of relapsed/refractory CLL

DR LOVE: Another question that occurred to me as you were just chatting about this real shift toward novel agents, is where chemoimmunotherapy is going to fit in, particularly in the relapse setting. What do you see happening in the future? I mean people are saying chemo is out. But is it really chemo is out first line but it’s going to be coming in more in relapse disease?

DR MATO: Great question, absolutely no data available to support use of chemotherapy following novel agents. What we’re finding from our studies is that once a patient seems to go on this track of getting a novel agent or an antibody, there are very few oncologists who are then switching back to chemo. I have all these patients in our database who got obina, then ibrutinib, then idelalisib, then venetoclax, 4 lines of therapy later. The expectations that chemotherapy would work well are unknown.

I think that these registries that are ongoing, and there are several. The ones I mentioned — the informed CLL, the core CLL — are all trying to capture these patients who go onto chemotherapy post. But from the clinical trials, once you come off drug you’re censored. We never know what they’re getting anyway.

But I certainly am keeping it in my back pocket. And for anyone who’s IgHV mutated, for example, and require a drug and they don’t have a novel agent option, I’m definitely not excluding the use of chemotherapy for those patients.

DR LOVE: I guess we should have mentioned though, in terms of the FCR versus ibrutinib, that I guess it’s not really clear in the mutated patients, kind of, whether there’s a difference.

DR MATO: Correct. The hazard ratio I think was something like 0.47. It was favoring the ibrutinib, but it was not significant. And that’s also true with ibrutinib versus BR, and that’s also true with ibrutinib versus obina/chlorambucil. The same is true for ven. There is no significant advantage that’s been detected yet in the mutated patients. It’s totally open question for discussion and debate.

Clinical experience with and management of ibrutinib-associated adverse events

DR LOVE: One thing I want to ask you about before we get into your cases. You hear more and more about musculoskeletal toxicities with BTK inhibitors, specifically ibrutinib. Can you talk a little bit about what we know about that right now?

DR MATO: Physiologically, we know nothing. There’s really not a lot of information to understand the mechanism of action, but clinically it is a major adverse event that seems to be leading to discontinuation of the drug, I think a little bit more front line than in the relapsed/refractory setting. And unfortunately, without knowing the mechanism of action, it’s very hard to know how to address it.

Some people, and this is me included, will dose reduce; others will hold the drug, rechallenge, sometimes rechallenge with corticosteroids onboard for a short period of time. But people are trying coenzyme Q. They’re using quinine. They’re discontinuing statins. There’s a whole list of potential things that could be tried. One of our fellows, Dr Joanna Rhodes from the University of Penn, did perform a retrospective trial looking at the experience from University of Pennsylvania of patients who developed arthralgias, and she presented that at ASH. And while there wasn’t a clear-cut risk factor that predicted arthralgia, and there wasn’t a clear strategy that seemed to work above all others, there were several strategies that she presented that seemed reasonable to try.

We do many of those things before we discontinue ibrutinib in the setting of arthralgia.

The other thing I will add is that if the arthralgias or the myalgias happen early, particularly arthralgias, I think sometimes they’re confused with gout. And so I’ve had a lot of patients who I start on ibrutinib, they complain of these really bad joint pains in the first, like, 2 to 6 weeks’ worth of therapy. And I really find that a short course of steroids, either taking a break or during the ibrutinib therapy, can quell the arthralgias and those patients go on to do just fine.

I think you have to distinguish whether or not they’re almost an immediate toxicity, and that’s possibly due to gout or whether they can occur much later on in the course. And that probably is a true treatment-related toxicity due to ibrutinib.

DR LOVE: What is a typical clinical story that you see? Where’s the pain? Is it related to exercise or time of the day or…? What happens?

DR MATO: Actually, the most common thing that I hear from patients is that the joints hurt in areas where they were previously injured. If they had a bad knee from osteoarthritis, for example, or some other joint — a shoulder that was injured previously — that pain seems to be exacerbated. That’s 1 common clinical scenario. They say they have joint pain, I’ll say, “Okay, is it in a place that was previously injured?” And they’ll be like, “You know what, I did injure that knee 5 years ago.”

DR LOVE: Wow.

DR MATO: That’s 1 story.

Another story are in the small joints. I’ll see the fingers and the toes are painful or the wrists are painful. That’s another common presentation that we see.

I think those are the 2 most common for me. And like I said, I think the small joint issue may be more related to gout without hyperuricemia, and the other one may be truly exacerbation of inflammation. Ibrutinib affects B-cells and T-cells. It certainly has pro-inflammatory effects and that may be part of the story.

DR LOVE: I was going to ask you, in terms of the immune effects of BTK inhibitors, ibrutinib now I think — is used for graft-versus-host disease. What do we know about the immune effects? And do you think the arthralgia you were suggesting, it might be immune-related?

DR MATO: It may be. What we’re learning more and more about these drugs is that, number 1, they are not pure inhibitors of whatever target we say their inhibitors are. Ibrutinib is not a pure BTK inhibitor; idelalisib, same thing with PI3K.

There are probably next-generation drugs that are slightly cleaner, but they’re also not pure inhibitors of a particular target.

Ibrutinib inhibits ITK. It inhibits and interacts with TEK family of kinases. It inhibits platelet function, for example. There may be cardiac targets for ibrutinib, which is where the A-fib may come from. They certainly have both pro- and anti-inflammatory effects that are very, very difficult to understand. And you mention graft-versus-host disease, which may be 1 way of addressing the potential mechanisms of GVHD.

Investigation of ibrutinib in combination with CAR T-cell therapy for CLL

DR MATO: On the other hand, ibrutinib is being combined with CAR T cells in lymphoma and CLL with the hope of activating T cells. And so it’s really not as straightforward, that it’s pro- or anti-inflammatory in terms of its mechanism of action, at least not to me.

DR LOVE: Ibrutinib with CAR T. I’m not sure I’ve heard that one.

DR MATO: Yes. There were at least 2 oral presentations at the last ASH meeting, ASH 2018, one of them was from a colleague at Penn, Dr Saar Gill, where the hypothesis, which had been born from the laboratory, Dr Marco Ruella, had looked at the combination of ibrutinib and CAR T and found that because of its effects on T cells and how it can shift the T-cell repertoire, that it may actually activate CAR T cells and may improve outcomes. And so not only has that been seen in the lab and in these small center trials — these single-center trials like Penn and others — same has been reported from MSK experience, but also now the larger trials are allowing patients on ibrutinib to receive CAR T with the hope that it may have them work better.

And certainly the CAR-T experience in CLL has not been as great as has been in lymphoma and has been in ALL, particularly pediatric ALL.

CAR Ts work in about a quarter or a third of cases, and we don’t really have long-term follow-up data, but certainly not the high proportion of patients we saw in pediatric ALL, for example. There’s certainly room for improvement.

DR LOVE: Yes. We’ve worked on a number of occasions with your former colleague, David Porter. And I always —

DR MATO: Oh, yes.

DR LOVE: I always thought CLL was going to be a bigger story with CAR T. I seemed like it was more that all the novel agents and all were making it less relevant. But you’re saying that it really wasn’t as effective. I’m assuming some of your patients were treated with CAR T when you were at Penn?

DR MATO: Yes. And I enrolled patients, for example, on that trial, and I was actually an author on that trial looking at CAR T plus ibrutinib. I think you’re right; it’s combination of the 2 things.

David Porter reported that 3-patient, I think, initial CAR-T experience in New England Journal of Medicine —

I think it was 2013 — unbelievably active in that small subset of patients.

DR LOVE: Right.

DR MATO: But then 2014, ibrutinib, idelalisib, obinutuzumab get approved and all of a sudden, it’s a very, very crowded space. CAR Ts can be expensive. They have a real toxicity profile — neurotoxicity, cytokine release syndrome, need for prolonged hospitalization — and so I think it became harder and harder to justify enrolling patients on those trials before they had exhausted all other options. And in 2013, all other options weren’t that long of a list. But in 2019, all our other options — we have 4 novel agents approved for CLL in 5 years, and we’re about to have a fifth and a sixth. And so, it’s a long list of agents to go through before you could justify a cellular therapy.

DR LOVE: It’s funny, I think people coming into oncology, maybe they don’t really see like how crazy things are right now. When we were at ASCO, I was showing the agenda from a meeting we did in lung cancer 5 years ago, 2014, and the word checkpoint inhibitors was not in the agenda. Five years ago.

DR MATO: And that’s incredible.

DR LOVE: Now it’s standard. That’s just lung cancer. CLL seems like it’s even more complicated.

Case: A woman in her mid-70s with del(17p) CLL and no IGHV mutation experiences arthralgia and hypertension during second-line therapy with ibrutinib

DR LOVE: But let’s talk about how this is really playing out in clinical practice and maybe we can just touch on these cases beginning with this 75-year-old lady.

DR MATO: This is a 75-year-old woman who had some comorbidities who was treated in 2014 borderline — early 2014 — with FCR. She had some high-risk features including a 17p deletion, which in 2019 would have mandated ibrutinib or venetoclax therapy for her, but at the time it wasn’t available. She did achieve a deep remission.

She had a CR, but she had persistent disease. And of course, like all patients who have high-risk features who receive chemoimmunotherapy, there’s a high rate of relapse. She relapsed and ultimately went on to receive ibrutinib as a standard of care. Of course that drug was initially approved in the relapsed/refractory setting in 2014 and then, subsequently, approved in the front-line setting for patients with a del(17p).

She goes on to receive ibrutinib, tolerates it reasonably well initially, but then she had some side effects. And I think the side effects that she had were significant arthralgias and hypertension, which is probably 1 of the most under recognized toxicities related to ibrutinib because plenty of people walk around with hypertension and have absolutely no symptoms at all from it.

The ibrutinib was dose reduced as a potential strategy for mitigating the arthralgia issue to 280 mg per day from 420, and right now she’s tolerating it just fine and has no recurrence of that particular toxicity.

That case really illustrates a lot of important points. Number 1, the standard of care has changed for del(17p)-positive patients. Number 2, toxicities can occur that are either clinically symptomatic or silent like arthralgia, symptomatic or silent like hypertension. And then the third is that it’s reasonable to consider dose reductions of ibrutinib in the setting of a toxicity before discontinuing the drug, and in this case, the woman went on to a lower dose to maintain her response but has not had significant morbidity from receiving ibrutinib.

Incidence and management of hypertension associated with ibrutinib

DR LOVE: The point about hypertension is really great. I don’t even remember people talking about it. First of all, what’s the mechanism?

DR MATO: Same answer as earlier with arthralgia. We don’t yet know the mechanism. Actually, at the EHA meeting, 1 of our fellows, Dr Lindsey Rocca,presented a poster on over 200 patients that she followed who received ibrutinib, where she estimated not only the rate of incident in hypertension, but the rate of hypertension exacerbation and how well oncologists and internists do in managing that. And actually the numbers are really impressive. There’s approximately 35% to 40% rate of incident in hypertension per standard definition. But I think the biggest area for improvement is that there are very few patients or a small proportion of patients who actually have appropriate management in the setting of hypertension.

We really need to work better with their cardiologists, or their internists, or do it ourselves to manage their hypertension.

She really couldn’t determine a pattern of which agent worked best for managing this ibrutinib-induced hypertension.

This is an area that’s wide open in terms of research, and she’ll hopefully be publishing that paper in the near future.

DR LOVE: This is really fascinating. We’ll follow it up. We do a lot of surveys of both investigators and docs in practice. And I can’t wait to ask people what they do. I’ll bet you most people give antihypertensive rather than reduce the dose like you did in this lady.

DR MATO: I think the answer is that most people do nothing. Because the patients don’t have symptoms, there’s a lot of people who say, “Go to your internist and address your meds. Come back in 3 months.”

DR LOVE: Oh, interesting.

DR MATO: Three months later, nothing happens. The other thing that’s interesting is if you look at the longer-term follow-up data that were presented by Susan O’Brien from the trials, the only adverse event that doesn’t diminish with time is hypertension. All of the other ibrutinib-associated AEs go down — like if you make it through year 1, the chance of having an AE is diminished. But hypertension, there’s a small proportion of patients per year that develop hypertension through at least the first 5 years.

It’s one of these potential AEs where it’s an issue on day 1, but it’s also an issue on year 4 that you need to consider.

DR LOVE: That’s really interesting. Because if you think about a typical situation where an oncologist will deal with hypertension of a side effect, it’s going to be either an anti-angiogenic — it’s going to be bev or a TKI — and again, the algorithm there is treat the hypertension and keep the drug going. And I think what you’re saying is, your algorithm is decrease the dose?

DR MATO: In this case, the dose was decreased because of the arthralgia.

DR LOVE: Ah!

DR MATO: My algorithm for the hypertension, and the same for atrial fibrillation is manage them appropriately medically. If a patient develops hypertension, I tend to not dose reduce.

DR LOVE: Ah! Okay.

DR MATO: But if they’re on 1 agent I add a second. If they’re on 2, I add a third. If I can escalate the doses I do. I work with their internist or their cardiologist.

I actually think you can keep them on full dose in the setting of A-fib or hypertension as long as you’re actually aware of the toxicity and managing it appropriately.

The reason to dose reduce is, for some reason you can’t manage them medically then you may want to think about that. But typically, we try to keep them on their treatment dose. In this case it was definitely dose reduce in the setting of arthralgia.

DR LOVE: Though it’s interesting, though when you dose reduced her because of the arthralgia, what happened to the hypertension?

DR MATO: Hypertension decreased and I do think there may be a dose toxicity relationship, but that hasn’t been studied and certainly that’s not published.

DR LOVE: Interesting.

Dose reductions of ibrutinib to mitigate side effects; effect on efficacy

DR LOVE: What do we know about the dose relationship between BTK inhibitors and efficacy? Do you lose anything by decreasing the dose?

DR MATO: I think the short answer is I don’t think so. We actually conducted a study, retrospective study which we published in 2015, I think, or 2016, in partnership with Georgetown and Hackensack where we looked at all of the patients in our system who had dose reductions of ibrutinib within the first 3 months of exposure who stayed on that lower dose and compared it all the patients who were on standard dose, and we couldn’t detect a difference in PFS, OS, or response rate. That data was published in BJH.

Subsequently there’s been a paper in Leukemia & Lymphoma, and there’s been some prospective data from MD Anderson published in Blood, which have confirmed our hypothesis that if you have to reduce in the setting of AE, you probably don’t lose much.

I don’t think that that’s a rationale for starting at a lower dose, but if you have to do it you can provide patients with a high level of reassurance. I think part of that may be mechanistically, but also part of that may be the fact that patients are not that large with CLL.

And the data from the Phase I suggest that if you do weight-based dosing you need to at least get to 2.5 mg/kg in order to have 95% occupancy of BTK. We measured our patients who got the low dose, and actually most of those patients, even at 280 mg a day, were still getting to 2.5 mg/kg, so they’re probably still getting 90, 95% BTK occupancy, although we didn’t test for that because it was retrospective.

But the data from MD Anderson that are prospective in, like, 11 patients do support that with time as you’re having a reduction in the tumor mass, you may require less drug in order to control the remaining tumor bulk or the number of cells that remain.

It’s an unanswered question, but I think low-dose ibrutinib, while not a standard of care, is reasonable in the setting of adverse event.

DR LOVE: You talked about some of the novel agent options, first-line therapy for the typical patient who’s del(17p) or p53 negative. What about those that are positive? Is it still ibrutinib or venetoclax a consideration?

DR MATO: I think both are equal considerations. I think we have more data available in aggregate for ibrutinib in del(17p)-positive patients, but venetoclax has been also heavily studied in that patient population. There’s a relapsed/refractory study, I think reported by Stephan Stilgenbauer, in del(17p)-positive patients. And to me, they’re equal efficacy in a del(17p) patient.

I don’t differentiate one versus the other. I think some people do, but I don’t think that there’s a difference.

DR LOVE: It’s been really interesting to hear about a lot of issues related to ibrutinib.

Case: A man in his mid-60s with a history of hypertension and atrial fibrillation receives acalabrutinib as first-line therapy for CLL

DR LOVE: Let’s bring in acalabrutinib, and I asked you to maybe tell me about a patient that you took care of who received that agent and you have a 67-year-old man. What happened there?

DR MATO: Okay. This 67-year-old — I guess the first thing I should say about acalabrutinib is that we do use it sometimes in CLL, but it’s not yet FDA approved. It’s an off-label use of the drug. It’s only really labeled now for relapsed/refractory mantle-cell lymphoma.

With that being said, this 67-year-old had enough medical comorbidities that weren’t that well controlled, that I had a concern about using ibrutinib. They had poorly controlled atrial fibrillation and hypertension. A decision was made instead of starting with ibrutinib to try to obtain insurance approval to use acalabrutinib.

One of the limitations of the drug versus ibrutinib is it’s a twice-daily dosing versus once a day, but the patient was started on the drug and tolerated it reasonably well.

A couple of things I wanted to highlight. One of the toxicities associated with acala that isn’t frequently seen with ibrutinib is headache. And so this patient did have a Grade 1 or Grade 2 headache during the first 4- to 6-weeks’ worth of therapy, which is relatively easily treated with acetaminophen. But the patients just need to be aware of that.

Headaches and hypertension associated with acalabrutinib

DR LOVE: I’ve heard that described as a tension headache. What do patients actually tell you?

DR MATO: Patients have actually described it as a headache unlike other headaches that they’ve had before. I think probably the closest is a tension headache. It’s usually like back of the head it seems like a little bit more. But there’s no pattern that I’ve seen with that headache. The main feature is that it’s not been severe. And in my experience at least, never limited me using the drug or having to stop it because of headache.

DR LOVE: I’ve heard from a number of people, including your former colleague Craig Moskowitz, who came down here to Miami where we are —

DR MATO: Mm-hmm.

DR LOVE: — talk about caffeine and these headaches. Have you seen that be helpful?

DR MATO: Yes. That is something that we have anecdotally recommended to patients. I actually think acetaminophen works the best.

Just a simple acetaminophen seems to be a good solution for people. And the main thing is to tell them is that it’s self-limited. And so I haven’t really seen this be an ongoing problem beyond a few weeks’ worth of exposure to the drug.

The second toxicity this patient had, which wasn’t so severe, but was hypertension. And the reason why I wanted to highlight this is that we have now had longer term follow-up data — I think the median follow-up was around 40 months, presented at ASH by John Byrd from Ohio State — where he looked at the acala experience. And 1 thing that was interesting was, while the AEs did not seem to be as much as we would have predicted with ibrutinib, although apples to orange comparison so you really can’t draw it, one thing we did learn was that they did see some A-fib, some hypertension, some bleeding with acala. Some of those BTK-mediated toxicities still need to considered.

Now we didn’t get to mention this earlier, but there has been a head-to-head trial of ibrutinib versus acala conducted in the relapsed/refractory setting, 1-to-1 randomization for patients with a deletion 17p or deletion 11q.

Those data will hopefully be presented in the next 1 to 2 years. That’s really fortunate because it will give us a window into whether or not there are differences in the activity or the AEs associated with these drugs. But until that time, I try to think them as similar in terms of what their potential toxicities are.

Anyway, back to this patient. They did very well. The drug controlled their disease. And fortunately, there was not exacerbation of atrial fibrillation, for example. No major issues long term at this point in time.

Comparative efficacy and spectrum of kinase activity with ibrutinib, acalabrutinib and zanubrutinib

DR LOVE: Can you contrast the pharmacology or the spectrum of kinase activity between acalabrutinib, ibrutinib and I know there are other BTK inhibitors out there, too?

DR MATO: Yes, there’s 3 main BTK inhibitors that are either approved or, in the case of the latter 2 being extensively studied in CLL and lymphomas — of course ibrutinib is approved front-line, relapsed/refractory. It has many lymphoma indications. It also has Waldenström’s. It also has GVHD. Pretty broad use of the drug in B-cell malignancies and GVHD.

The other 2 are acalabrutinib, which does have an approval for mantle cell, and zanubrutinib, or BGB-3111, which is being studied and does not yet have an approval, but we do have the prospect of seeing some randomized data in the near future.

The kinome or the kinase maps for ibrutinib and these drugs have been compared, and it does seem that there are many, many more targets associated with ibrutinib relative to the other 2 drugs. The other 2 appear to be a more clean or pure, however you want to say it, BTK inhibitor relative to ibrutinib.

I think to automatically assume that a more pure drug or a more clean drug is better than a “dirtier” drug, I think is not founded in reality. Probably some of the best aspects of ibrutinib’s activity may be related to its off-target effects, particularly in the GVHD, for example.

I think that the mapping of what kinases are inhibited by these drugs is completely preclinical. And I think you and I would both agree what happens in a lab or in a test tube oftentimes is not mirrored in patients. And so we do have head-to-head data for acala versus ibrutinib coming out. And there are also head-to-head data for zanubrutinib versus ibrutinib that will be coming out.

I think from the perspective of clinicians, what happens in patients is most relevant. We’ll see what those data show us if there are any differences or if the AE profiles are more similar than dissimilar.

Activity and tolerability of acalabrutinib versus ibrutinib

DR LOVE: In terms of, kind of, what it seems to be at this point indirectly, what about arthralgias in acalabrutinib?

DR MATO: They seem to be less commonly reported, but then again, it’s hard to know. It’s a relatively smaller patient population. And a lot of the AEs associated with these drugs really come out beyond the small subsets of patients treated in clinical trials.

One example, our group at Penn reported on 4 cases of ibrutinib-related pneumonitis that we published in Blood, I think in 2015 or 2016. Those cases were all observations from our clinic. We went on to confer with other centers that this is something that is rarely seen as an adverse event. But if you look at just the clinical trial literature, that’s not something that was highlighted or observed very clearly from the clinical trial experience.

I don’t know. I think a real-world study in acalabrutinib is warranted, especially since there’s a lot of off-label use of that drug, particularly in CLL. And I know my colleagues at Georgetown, Dr Cheson and Dr Yazdy, are conducting such a study right now. Hopefully at the next ASH meeting, we’ll have some data to report.

DR LOVE: Interesting.

What do you think the likelihood is that there’s going to be a difference in efficacy between ibrutinib and acalabrutinib?

DR MATO: It’s really hard to speculate. Probably the most common people who’ll want to answer that question are people who are investors, trying to decide 1 drug versus the other. I really have no idea. I’ve had mostly favorable experiences with both drugs, and it may be that they’re most close together than they are dissimilar from one another.

We’re fortunate to have this wealth of riches of novel agents in CLL, where it’s oftentimes, when I talk about ibrutinib versus venetoclax or ibrutinib versus acalabrutinib, that we’re picking among all winners. These drugs are all active. Have improved life for patients. Have, in many instances, improved survival. If you were asking me to choose between like chlorambucil and ibrutinib, I could sit here and go on and on and on about why I feel 1 drug is better when there’s such an obvious difference in activity. But until we see the randomized data, it’s really hard for me to speculate and give an opinion that actually is based on fact.

I think we have a wealth of riches, and we’re choosing between winners very often.

Case: A woman in her mid-50s with von Willebrand disease and CLL receives venetoclax after experiencing disease progression through several lines of therapy

DR LOVE: I want to hear about this 55-year-old lady with von Willebrand disease who got, it looks like she got what, venetoclax eventually.

DR MATO: Yes.

DR LOVE: She had other therapies. I’m really curious, particularly in terms of how you managed her once she started the venetoclax, can you talk a little bit about this patient?

DR MATO: Sure. She’s a really very lovely patient who has been treated with several lines of therapy. She, of course, started with chemoimmunotherapy prior to the approval of novel agents and, at least historically, she got FCR and then BR. And I actually met her while she was receiving idelalisib/rituximab in the context of a clinical trial. I actually remember the exact moment when I heard about her case because I was at ASH learning about CLL and she was presenting to our emergency department as a new patient to us who I’d never met before. And at the time she was receiving idela, she was starting to progress, but more importantly she had had these respiratory symptoms that ultimately turned out to be a PCP pneumonia.

That is a known potential risk associated with novel agents. They can develop opportunistic infections.

DR LOVE: Could I just ask about that?

DR MATO: Yes.

DR LOVE: Because when I saw that in the history, when I have been thinking about pneumonitis and PI3 kinase inhibitors or idelalisib, I thought it was immunologic and not infective.

DR MATO: Yes, that’s the thing, is that both are possibilities. And so if you have a patient who’s short of breath and hypoxic on idela for example, I personally think they need to be admitted, they need to be bronch’d. Because you can’t radiologically distinguish one from the other, and I’ve seen cases of both in the setting of PI3K inhibitors and also BTK inhibitors. There is an experience published in Blood from the NCI looking at PCP in patients who were receiving ibrutinib.

In this case, we admitted her. We bronch’d her. We had ID see her and it turned out the bronch was positive for PCP, which, in some ways, is easier to deal with because we were able to start her appropriately on steroids and on sulfamethoxazole/trimethoprim. She was able to get that under control. And then we wanted to get her treated with a novel agent. Unfortunately, venetoclax was not yet approved at the time, but we did have obinutuzumab.

She had symptomatic disease. Her spleen was the major issue — always, always has been. And so we gave her 6 cycles of obinutuzumab without chlorambucil — she elected to not receive that. Got her disease under relatively good control. Spleen was smaller but not completely improved. And then fortunately, I can give you so many different examples, that a drug gets approved nearly at the moment that a patient needs to have access to a new agent. This happens all the time in CLL. Fortunately, we had —

DR LOVE: That’s because things are getting approved all the time in CLL.

DR MATO: Yes. It’s great. I mean, CLL is 1 of the best areas to be in oncology because there’s tremendous hope and every month I feel like I’m telling patients about some new advance, which is really quite different than the pioneers in the field — Dr Rai would come to mind who had to have very limited tools available to him to help his patients. Right now things are a lot different than they were 20 or 30 years ago.

DR LOVE: Yes. We —

DR MATO: But anyway —

DR LOVE: There were like 100 prognostic variables out there that nobody looks at anymore.

DR MATO: It’s true. I think this is 1 of those examples where prognosis and biology proceeded advancement in terms of therapeutics.

I mean Ehrlich was talking about the B-cell receptor in like 1902. We didn’t get an agent available to inhibit a B-cell receptor mediated protein for another 114 years.

Sometimes we understand biology long before we understand how to deal with biology.

But anyway, venetoclax became available for this patient. She received it as a monotherapy, relatively well tolerated. She’s had some minor hematologic issues. But I can tell you, she is still in remission on venetoclax as a monotherapy. Fortunately, we have now CAR-T trials available and bispecific antibodies available. I have a back-up plan for what might come next if she progresses. But if we could go back in time and set the stage for 2012 or 2013, I don’t think this lady would have survived if we didn’t have these novel agents available that we did over the last couple of years.

Anyway, she’s doing great, leading a very active life. She’s had a couple of issues with hypogammaglobulinemia. She receives IVIG but otherwise is actually doing very well.

Dose adjustments of venetoclax and management of TLS

DR LOVE: How did you actually manage starting the venetoclax in her?

DR MATO: When venetoclax was first approved, we were a little bit more conservative. We did the ramp up in the setting of hospitalization for her. I think now she would probably be deemed medium risk and I would probably do it completely in the office. But we admitted her once a week for 5 weeks. We gave her allopurinol, IV fluids, monitoring labs at our time point 0, 4, 8 and 12 and 24 and just slowly escalated the dose between 20 mg and 400 mg.

I think if the office is not equipped to do it, it’s always reasonable to do it in the hospital, although I think more and more, once you’ve done it a couple of times it’s relatively easy to do it in the office setting as long as you have a stat lab available to you at an 8-hour time point.

DR LOVE: I was going to ask you, when you talked about your real-world look at venetoclax, the package insert with that table about what to do with TLS based on the white count and the nodes and all, it’s up in your face. I think most people look at that. But one thing I wonder about — and I think you kind of alluded to it — is how closely people look at renal function. Because, like in the package insert, to me it doesn’t emphasize it enough that it’s a critical issue.

This lady is 55. I imagine she had normal renal function. But how much of an issue is renal function in your decision about what to do about preventing TLS?

DR MATO: It’s becoming more and more of issue because if you look at the package insert, there’s not a lot of guidance on how to stratify patients based on renal function. I think the creatinine clearance cutoff that they put in there is 80 mL per hour is the cutoff that’s in the label.

Actually, our fellow, Dr Rocca, published a paper in CCR where she looked at patients based on their TLS risk for per the label, low, medium and high risk, and then added renal function stratified by less than 80 versus greater than or equal to 80 to see whether or not renal function impacted the risk of developing clinical or laboratory TLS. And the short answer was that it did. It was an independent predictor in her model. And that’s only using 80 as a cutoff. That’s all we had in our data set. We would love to look at other cut points. But it was an independent predictor.

The odds ratio was somewhere between 2 and 3. And she actually went on to do ROC analysis looking at the area under the receiver operator characteristic curve. I think it was like 65% for the FDA label — low, medium, high. And if you added in renal function, it went up to 79% or 80%.

Thinking about renal function I think is critical when you’re deciding whether a patient could be outpatient or whether or not they should be hospitalized. And I’m hoping we’re going to do some more research on that topic.

DR LOVE: Yes, I think there are a fair number of people with creatinine clearances in the 40 to 60 range and I don’t know what you do with them.

DR MATO: We do our standard risk stratification and then we decide very carefully, patient-by-patient basis, whether we hospitalize or not.

DR LOVE: Whether you bump them up, sort of.

DR MATO: Yes. Or if they live 3 hours away, I put them in the hospital. If they live around the corner, I feel more comfortable maybe managing them outpatient. It really depends on the patient.

Case: A woman in her late 80s with del(13q) CLL with IGHV mutation, symptomatic anemia and lymphadenopathy receives first-line obinutuzumab

DR LOVE: I always like to see a case start out with “88-year-old patient” because I’m always curious about managing people as they get older. What happened with this patient?

DR MATO: This is an interesting case because we’re seeing more and more older patients with CLL who are eligible for everything. And it used to be that patients who were older really were relegated to receive rituximab monotherapy, which isn’t labeled, or chlorambucil. But now we’re seeing patients who come in who have some aspect of symptomatic CLL and I feel very comfortable offering them multiple treatment options. In fact, most of the same ones I would offer a 55-year-old.

This patient was eligible to receive chemoimmunotherapy. They could receive ibrutinib. They could receive potentially venetoclax-based therapy today. And we also talked about the CLL11 data, which was chlorambucil plus obinutuzumab, which was compared to either rituximab/obinutuzumab or chlorambucil, positive trial for the primary endpoint.

This patient elected for obinutuzumab by itself because of the fact that it was time limited — 88 years old, didn’t want to be on a “life-long therapy.” Was hoping to get 6 months’ worth of therapy and then stop. And actually, this patient did very well with the exception of minor infusion-related reactions, which I would argue during the informed consent process should be just discussed as a reality for almost all patients.

They tolerated the drug well. Had some issues with cytopenias in the second cycle, but, overall, got through all 6 cycles and had a two-year remission, which is very, very, I think, relevant for somebody especially at that age point. And then ultimately, when they progressed a couple of years later, which might be the expectation in terms of the median from the studies, they were able to then go on to receive ibrutinib-based therapy and do quite well.

I think this case is a great example of the fact that years ago therapies were really largely stratified based on age and performance status. And as we understand how to target the disease better, more and more doors are open to patients with comorbidities or patients with advanced age.

DR LOVE: I see that she had a little bit of a Grade 2 infusion reaction.

Clinical experience with obinutuzumab-associated infusion-related reactions

DR LOVE: Can you talk a little bit about your experience with infusion reactions with obinutuzumab, including in older patients? And I guess now with venetoclax/obinutuzumab, it’s going to be more of an issue.

DR MATO: Yes. I don’t see more infusion-related reactions in older people, but I think the risk to older patients is higher, mainly because they probably don’t have the same organ reserve, either their ejection fraction or their pulmonary function, in order to deal with a significant IRR or to deal with the fluids needed where you may want to hydrate these patients, for example, in the setting of receiving an antibody.

You do the best that you can in terms of premedicating patients with antihistamines, acetaminophen, corticosteroids. There’s really ample evidence and guidance available in the label for obinutuzumab as to how to manage the prophylaxis or the prophylaxis for infusion-related reactions.

Certainly as part of informed consent you have to discuss that there’s probably a 70% or 80% chance that you may see at least some minor issue. The most important aspect of it is being present to manage it, having a staff that are familiar with them, and knowing when to stop the drug.

And so the way the drug is supposed to be given, it’s a split dose the first week. You get 100 mg day 1. You get 900 mg day 2. Plenty of times, if I have a patient who has an IRR day 1, they get 50 mg into it, we oftentimes decide not to give day 2 and then just to resume week 2. And if they started with a white count of 200,000 week 2, 9 times out of 10, they come in with a white count of 30,000 or 20,000 and they do just fine.

Like, forcing it and requiring patients to be mandated to get through that 1,000 mg in the first week, I think that’s the goal. But, in reality, you think about the patient, and given none of these therapies are curative, the goal is to control the disease and sometimes you may not be able to get the full dose in the first week or two. And patients can still do very well with that strategy.

DR LOVE: You mention that she’s on ibrutinib. How did she do on ibrutinib, any tolerability issues?

DR MATO: In this particular case, no.

DR LOVE: Nothing.

DR MATO: She’s tolerating it okay.

Choice of first-line therapy for older patients with CLL

DR LOVE: Just out of curiosity, if she or somebody were to present with this exact situation today, 88 years old, what would be your likely therapy?

DR MATO: You mean as a first therapy, or…?

DR LOVE: Yes, first.

DR MATO: Okay, for —

DR LOVE: Yes. If this same lady were to present for first-line therapy.

DR MATO: I’ve taken chemoimmunotherapy off the table for a patient like this. Because of the iLLUMINATE data and the data from the Alliance trial, like I’m not really enthusiastic about giving BR or obina/chlorambucil to this patient.

I’ve shifted a little bit more towards recommending either venetoclax or ibrutinib to a patient like this. Although, I still think that if they’re looking to just have some quality-of-life improvement, address some symptomatic aspect of their disease, I still think obina is reasonable to consider, just discussing that we do have now some randomized data from ibrutinib and venetoclax-based therapies that show that those are better.

DR LOVE: It’s interesting because this patient, also the previous patient, actually earlier on got obina without the chlorambucil. How often do you do that? Kind of, from the beginning, I started to hear people talking about and questioning, really, what chlorambucil was bringing to the table.

DR MATO: Yes. I mean it’s an off-label decision, so I have to say that the label mandates to give chlorambucil. I really don’t think it adds much but toxicity, and so my own practice is to discuss that with patients and offer them the chlorambucil, but if they’re not interested in it, based on the AEs, I’m perfectly comfortable with giving the obina as a monotherapy. I would say that’s 95% of the time or more. And I’ve seen outcomes that, at least in my own judgment, are comparable to what is achieved with the addition of the chlorambucil.

DR LOVE: There’s not inconsequential amount of rituximab monotherapy used in community-based practice for CLL. How would you compare the efficacy of rituximab to obinutuzumab clinically? Not so much research data, but what you’ve actually seen?

DR MATO: I think obina is more active. I really do. I think that rituximabas a monotherapy, its main role is largely for treating autoimmune hemolytic anemia, which can be associated with CLL or ITP, which can be associated with CLL.

Outside of that, to be honest with you, I think that the experience I’ve had with obina is that the remissions seem to be longer lasting. It may be a dosing issue because you’re giving more mg of obinutuzumab over 6 months than rituximab, but we have what we have from the trials and what we do in practice. And so I very rarely will give rituximab as a monotherapy, again outside of the window of an autoimmune-mediated cytopenia.