Treatment Options for Younger, Fit Patients with Chronic Lymphocytic Leukemia (CLL) — Paul M Barr, MD

DR BARR: Well, thank you for allowing me to present my thoughts on considering treatment options for younger, fitter patients with CLL today. And to start we’ll just cover a few points about the pretreatment workup. These are the treatment indications currently from the iwCLL classification. We still think these are incredibly important so we don’t expose patients to unnecessary side effects. There are some early interventions that are ongoing, but until these read out it’s still important to know these treatment indications and to observe them.

When patients do meet one of these treatment indications, we recommend still following the iwCLL Guidelines in terms of recommended testing prior to treatment. And you can see the different tests listed here on the left and the recommendations from the group on the right. I think I’ll point out that the molecular characteristics are always changing and therefore I think cause confusion with community physicians.

The IGHV mutational status, FISH panel, and TP53 mutation testing are the ones listed as always currently. Personally, I usually check these 3 at diagnosis because it helps patients in terms of a discussion in terms of prognosis, especially if they’re going to be followed closer to home and not followed at our center for every visit. But as patients get closer to treatment it is important to repeat a FISH panel and TP53 mutation testing.

Note that conventional karyotyping is considered “not generally indicated”. There is a caveat there, that this can be useful prior to therapy if it can be reliably performed in your center. So something to consider. And this may change over time.

And these are just the survival curves that justify these recommendations, showing outcomes from mostly the chemotherapy era. The panel on the left shows that the patients with unmutated IGHV genes often have a more aggressive disease course and worse prognosis. The middle panel shows you the dismal outcomes we used to see with patients with deletion 17p. And on the right you can see that patients with TP53 mutations often have poor outcomes that are similar to those with deletion 17p.

So now just to focus on clinical trials, and I’m really going to dial in on the 2 that led to the approval of our standard BTK inhibitors, focus on those 2 for this talk. But by way of background, just to point out, I think most are now aware that about 60% or so of patients with low-risk CLL, meaning those with IGHV-mutated genes, can achieve “a functional cure” with FCR, while those with unmutated IGHV genes we would expect a median progression-free survival in roughly the 4-year range.

Early data with ibrutinib suggested that it may compare favorably with FCR. And so this led to the RESONATE study, which enrolled patients that were older, compared ibrutinib against chlorambucil. And this is the 5-year follow up from the RESONATE-2 study, showing us that about 70% of patients remain without progression after 5 years. And this translated into an overall survival benefit, as we all know. Note that only about 6% of patients have come off of ibrutinib for disease progression in this study so far, but almost 30% have come off for adverse events, for side effects in essence.

So this sets the stage for the E1912 study, the North American Cooperative Group study, that enrolled patients that are 70 years or younger and that were otherwise fit. The study randomized patients in a 2:1 fashion to ibrutinib until disease progression, combined with 6 cycles of rituximab, compared against 6 cycles of FCR. And key points to point out, that the study excluded patients with deletion 17p. Note that a few of the patients did ultimately have TP53 mutations found on sequencing later on. The median age was relatively young at 58 years, and about 71% of patients were unmutated.

The initially-identified PFS benefit held up at the last data cut. The 3-year PFS rates were 89% at the last ASH for ibrutinib/rituximab compared to 71% for FCR. And the overall survival benefit held up as well, which to me is actually pretty fascinating. I would not have predicted an overall survival benefit in this study, given all the good efficacy of FCR and the other treatment options that we have. But if you look at the events on those OS curves, the events that led to death, the most common was secondary malignancies. And I think that accounted for maybe 4 events in the FCR arm. And there were another 4 that were attributed to CLL, which is a bit surprising. But nonetheless, this might suggest that it’s important to choose wisely in the first-line setting, to really think about our first-line treatment options.

On subgroup analysis the majority of the PFS benefit occurred in the IGHV unmutated patients, shown in the right panel. But it’s also interesting to look at the left panel to look at those IGHV-mutated curves. The IR arm continues to track above the FCR arm. The differences aren’t significant, but nonetheless I do think it is interesting to see how well IR is performing in these patients. We will have to see how they mature over time, as you would expect that more patients on ibrutinib would come off as the years go by.

I think there’s been a lot said about the difference in side effects with a lot of the novel agents, and these are the severe treatment-related AEs in this study. And again, I don’t think it’s surprising that there were more cytopenias and infection events in the FCR arm, while there were more arthralgias, diarrhea, as well as bleeding, hypertension, and AFib in the ibrutinib arm.

But it’s important to understand what happens to patients when they come off of ibrutinib. There’s a number of anecdotes describing how patients can have rapid disease progression when ibrutinib is stopped for an AE, and I think these data show that if there’s good disease control this may not necessarily be the case.

This curve represents the 72 patients who discontinued for reasons other than progression or death. And after a median time on therapy of 15 months the median PFS after discontinuing was about 22 months. So this tells us that it may be very feasible to watch patients, to observe them after discontinuing ibrutinib if the disease is well controlled.

Now switching gears to acalabrutinib. This is a more selective BTK inhibitor with less off-target kinase inhibition. As you can see, based on the IC50s on the right-hand side of the page, and also it has a shorter half-life, about an hour, which allows for BTK resynthesis, less target occupancy. And so as a result acalabrutinib has to be dosed twice daily compared to once daily for ibrutinib.

And this is the study that led to approval of acalabrutinib in the first-line setting, the ELEVATE treatment-naïve study. It enrolled patients that were predominantly older than 65 years. There were about, I think, 15% of patients that were younger and had comorbidities that were enrolled as well. And the primary comparison was between acalabrutinib given until disease progression with 6 cycles of obinutuzumab, against 6 cycles of obinutuzumab/chlorambucil. There were secondary comparisons against that middle arm, which was single-agent acalabrutinib. And additional points here. Again, this was a study that the median age was 70. 9% of patients had deletion 17p, 11% with TP53 mutations, and 63% were unmutated in terms of IGHV genes.

And these are the PFS curves. I think no surprise to anyone that there was a huge difference between the acalabrutinib arms and chlorambucil/obinutuzumab. If you look at the 2-year PFS for acalabrutinib it’s 87% on the slide. And this is very similar, if not identical, to what we saw in the ibrutinib studies at 2 years, as well as, for what it’s worth, comparing against venetoclax/obinutuzumab in the CLL14 study. I think what is distinct from the ibrutinib studies is the difference between the 2 acalabrutinib arms. Acala/obinutuzumab seems to be provide a little better PFS, even though the study really wasn’t powered for this comparison.

In the Alliance and MD Anderson studies, which randomized ibrutinib against the combination of ibrutinib and rituximab, there really did not look like there was any benefit for adding rituximab. So it’s not clear if this is related to acalabrutinib being a better BTK inhibitor partner or if obinutuzumab’s a better antibody or both. But for what it’s worth, when I use acalabrutinib in the clinic I’m typically not adding obinutuzumab right now, as there are a few extra side effects that we’ll get into a little bit. And also, it’s just nice in the current era to keep patients out of the infusion center if possible.

These are the different subgroup analyses from this clinical trial. And if you look at the forest plot, really all of the comparisons, for the most part, favor the acalabrutinib arms in patients with bulky disease, deletion 17p, deletion 11q, unmutated IGHV status, and complex karyotype. The one outlier, perhaps, is the comparison between acalabrutinib and chlorambucil in the mutated patients. Pretty similar number of events there, 10 versus 14. And this might support the benefit of the antibody in the mutated patients, but obviously it’s pretty early on. And we’ll see what happens in terms of the events over time.

Most patients in this study enjoyed a very good overall survival so far. So the curves look pretty similar. But I will point out one comparison that has a trend towards significance, and that’s comparing the overall survival of acalabrutinib/obinutuzumab arm against the chlorambucil/obinutuzumab arm. You can see the p-value is 0.0577. Not significant, and obviously early on, but here again half the patients crossed over from chlorambucil when they progressed to acalabrutinib. And we’re still seeing this trend. So here again, maybe this suggests the importance of choosing wisely early on, incorporating the novel agents into first-line treatment regimens.

These are the most common adverse events, and kind of a busy slide, but just wanted to make a couple points here. I think that most that have used acalabrutinib are aware of the fact that 40% of patients can have headaches when initiating the drug. These are manageable. They do improve over time. Otherwise you can see there’s a difference in diarrhea between acalabrutinib and chlorambucil, and I don’t think that’s surprising, now having used BTK inhibitors for a while. And there is a higher rate of neutropenia with the addition of obinutuzumab. Something to keep in mind if you do use the antibody.

These are the AEs of special interest. The BTK inhibitor-related side effects that we worry about. And you can see the rates of AFib, hypertension, and bleeding are fairly low in this study, which is encouraging. And obviously we try to compare against the ibrutinib studies. If you look at the RESONATE trials, those are the 2 studies that led to the approval of ibrutinib in the relapse setting as well as in the first-line setting, the rate of major bleeding at 5 years is about 10%, AFib was about 15%, and hypertension was about 20%. And obviously those numbers look very different from what we see on the page, but the follow up’s so much longer. And they are obviously different clinical trials.

So what I’m trying to do here in this slide is compare a couple clinical trials and compare the severe adverse events with trials that have relatively similar lengths of follow up, starting with the IR, the ibrutinib/rituximab, arm from the E1912 study with the same arm from the Alliance study. You can see that there are very different median ages of the patients enrolled because of how the studies were designed. And then if we look down at the side effects, I think the point here is that younger patients have less infection, risk for AFib, bleeding, and hypertension, and as a result more patients are likely to remain on ibrutinib over time, which you can see in the bottom row.

Now if we compare the IR arm from the Alliance study, which enrolled older patients, obviously, comparing this against the acalabrutinib/obinutuzumab arm from the ELEVATE study, the median ages are very similar. I think one could argue that the difference in the different antibodies could confound comparisons, obviously. But if we really focus on the BTK inhibitor-mediated events there does look like there are lower rates of AFib and hypertension in particular. The severe bleeding rates are, I would say, pretty similar at 2% versus 4%. For what it’s worth when you prescribe acalabrutinib it does feel like there’s less bruising. So we’ll see how these rates hold up over time. But altogether you can see that a higher percent of patients, again, with the caveats of comparing across studies, look like they remain on the BTK inhibitor, remain on acalabrutinib longer at this current follow up.

So trying to put it all together, these are the treatment options we would consider for younger, fitter patients. And I listed the 2 BTK inhibitors administered indefinitely on the left-hand side, and some time-limited options on the right-hand side. I think when you’re deciding on a treatment option for younger, fitter patients the discussion often is less about choosing the right option around comorbidities and more around what are the goals of care, really participating in that shared decision-making process to figure out what’s best for the patient.

And so when having that discussion I think what favors acalabrutinib might be convenience over say venetoclax/obinutuzumab certainly, avoiding the infusion center. It’s probably not the most clinically relevant point, but there is the PFS benefit, we think, of adding an anti-CD20. And acalabrutinib does look like it has less side effects than ibrutinib. Favoring ibrutinib are certainly the longer follow up, the more Phase III data. There are Phase II data supporting the efficacy of venetoclax after ibrutinib versus more anecdotal and retrospective data on the reverse. Ibrutinib is certainly convenient at once-daily dosing and is easier to administer in conjunction with the gastric acid-reducing medications. Acalabrutinib should really be avoided in patients on proton pump inhibitors.

Now on the time-limited therapy side, I really didn’t get into the data revolving around venetoclax/obinutuzumab, but I do think this is a treatment option perhaps for some younger patients, given that time-limited options may be in their best interest. And there really isn’t any reason to believe that these agents wouldn’t work in younger patients. The benefits here being the ability to achieve deeper remissions and discontinue therapy. This may help us avoid selection for resistant clones, perhaps. And there probably are fewer long-term side effects when you’re able to discontinue therapy. In terms of FCR, I think one could argue that it’s still a treatment option for those mutated patients, perhaps, and there certainly is less cost overall.

So moving forward, these are some of the randomized studies that are ongoing enrolling younger, fitter patients. And they obviously look pretty similar because one of the primary goals is to develop perhaps limited-duration therapies where we can achieve deeper remissions and avoid the cytotoxic agents. And you can see they’re being compared against BTK inhibitors administered indefinitely. So obviously a lot more work to come as we try to figure out the best treatment options for these patients.

So moving onto a couple cases that I’ll present here to hopefully hammer home some of these points. I tried to pick a few cases, or a couple cases specifically, that might be somewhat debatable, that again bring up some of the difficulties in treating younger patients. Case 1 is a 55-year-old man who had been complaining of fatigue for a good amount of time, at least a year and a half, very active person, police officer, who exercises daily.

And during the workup with his primary physician, a CBC was performed. He was found to have CLL, really had a normal hemoglobin, good platelet count. Risk factor testing revealed mutated IGHV genes and deletion 13q. And the patient did have diffuse lymphadenopathy on exam, which he described as having been there for perhaps a long time, not surprisingly.

Looking back at some of the CBCs on the bottom left there you can see that he certainly had an elevated ALC, but relatively normal hemoglobin, a little bit of fluctuation in the platelet counts.

And so with a patient like this I personally think it’s very important to get to know the patient a little bit and not jump into therapy, given the implications over the long term. So we had a lot of discussions about, like I mentioned before, the shared decision-making process, what’s best for him. But it really became clear that the patient had significant fatigue that was making it hard to work.

So we really spent some time discussing the treatment options and ultimately felt that a clinical trial would be in his best interest, and he enrolled on the E1912 study. The pretreatment workup demonstrated this diffuse lymphadenopathy. I think he felt it was most prominent in the neck, most noticeable for him. Bone marrow involvement was modest, and the patient was randomized to ibrutinib and rituximab. He started therapy, had rapid clearance of the lymphocytosis, as you can see in the bottom there.

And as he started ibrutinib I was very happy that we had the thorough treatment discussions because we really went through all the potential side effects, and he had a lot of them. He had transient oral sensitivity, but then some persistent diarrhea, GI upset, muscle cramping that really made it hard for him to work out, and as the years went by, developed some hypertension as well. And he started with a number of symptomatic measures on his own. He started on probiotics, tried tonic water and honestly felt that it did help some of the muscle cramping.

But as some of the side effects persisted, we did try a dose hold for a week or 2 to figure out how much of this was really related, and clearly the diarrhea did get better. He felt that that muscle aches did get better, somewhat, with holding the drug. But as time went on, we have a patient who’s now going through all of these gymnastics to try to control the side effects and was taking loperamide daily, a proton pump inhibitor, ultimately was on an antihypertensive, after a year of therapy the patient’s responding well. And ultimately, again, over many discussions, we dose-reduced ibrutinib once, and then a second time to 140 mg. And that’s what he continues on right now. The patient feels that he has less muscle cramping, less diarrhea. He’s not using loperamide daily. He is on 1 antihypertensive, which is controlling the blood pressure, but he’s off the PPI.

So I mean I think this demonstrates the importance of, again, really talking thoroughly with the patients, going through some of these measures. Honestly, I think some of the options that we give didn’t have early on now include stopping therapy and considering another agent. But one of the things that we’ve discussed recently is he’s responded well, should we stop and just observe? He prefers to continue on, but I think stopping would be very reasonable, and restarting an alternate agent in the event of progression later on would be another option.

So this is the second and last case, a 58-year-old diagnosed with CLL in 2014. He had minimal lymphocytosis. And then in 2015 the patient developed isolated thrombocytopenia. And so I think the suspicion of the treating oncologist at that time was clearly ITP, rightfully so. This is an event that often happens early on in the disease course. You can see the platelet nadir was about 27,000. And the patient was treated with prednisone, which did work. ITP recurred a couple years later, more prednisone, was given more rituximab at that point, which again he did respond. But a year later, again, more recurrence of the thrombocytopenia.

A bone marrow biopsy was done at that point, which supported the diagnosis of ITP. This time the patient got prednisone and 2 years of rituximab, and as the rituximab’s being weaned thrombocytopenia occurs again.

So the patient was referred recently because of this, and at this point he’s 64 years old, has hypertension, obesity, sleep apnea, renal insufficiency. He did respond before referral to a few days of dexamethasone, and you can see that the platelet count rose from 9,000 to a very nice 88,000.

So he responded well, but as soon as this was stopped the platelets started dropping. And so we looked at the risk factor testing, and the patient had unmutated IGHV genes and deletion 13q. And ultimately, after discussing the options, we started the patient on acalabrutinib. And it looks like he is responding well, and the platelet count is well controlled. And I think this is one of the take homes here. I think there were many options for this patient, and I think some might even argue that we should continue just managing him like isolated ITP.

But I think I personally have just been conditioned that in the setting of CLL if ITP or other autoimmune phenomena are difficult to control often patients will respond very well to BTK inhibitors. Everything just gets better when you start controlling the disease. And there’s some data from the RESONATE trial that support this. So I think that’s a good take home on this case, that if in doubt, treating the disease with one of the novel agents can really control the secondary problems.

DR LOVE: That was awesome. Really great presentation. I just want to ask just a few follow up questions. One thing I was curious about. Earlier on you were talking about the issue of the karyotype assay. Could you talk a little bit more about that and what the problems are in doing the assay? And from a clinical point of view what are the implications?

DR BARR: Sure. So I think one of the difficulties in CLL patients is that the CLL cells aren’t dividing at a very proliferative manner, and as a result, in the test tube it’s hard to find metaphases, and so karyotype analyses often fail. The solution was to stimulate the cells to divide. But there were concerns early on that this would induce abnormalities that were artificial. And so the testing evolved so that karyotype stimulation became standard. It became validated across a number of centers, but it isn’t easy to do. You really need to have an experienced cytogeneticist. And that’s not always available.

So part of the problem is technique. Another part of the problem is the data is a little bit mixed. Not all complex karyotypes are equal. There are some combinations of 3 abnormalities that aren’t necessarily unfavorable. And I think this really came out in the Alliance study, that’s the study that enrolled older patients and compared ibrutinib to ibrutinib/rituximab to bendamustine/rituximab in older patients. There really wasn’t a prognostic or predictive benefit of complex karyotype in that first-line study. So it just shows that there are some limitations in the assay. I do think, for the most part, it is predictive in the relapse setting, especially when you have 5 or more abnormalities. And I think that’s why the iwCLL Guidelines suggest that it may be useful, but it wouldn’t consider it a standard assay that has to be checked in every patient.

DR LOVE: How would an oncologist in community-based practice decide whether or not their assay’s being done correctly? And how would they approach treatment decisions based on the results?

DR BARR: Sure. So I think in community practice often karyotype analysis is sent out. So understanding if the vendor is using CpG stimulation is probably the best decision-making factor. Sending it to a university-based academic center that has validated tests is probably the best answer.

So I think if you’re comfortable sending out, looking at the results and acting, the best way to use the results are to consider getting the assay in relapsed patients, and if there are 3 or more aberrations, considering that patient to have perhaps a poorer prognosis. Note that often what drives the complex karyotype are TP53 aberrations. Those are often responsible for leading to the poor outcomes, and so that would allow the treating physician to have that discussion with the patient that I’m a little bit worried here. Your outcomes may not be what we had talked about in the past. We really have to stick with the novel agents, but we may have to consider referral for clinical trials. If the patient’s younger, considering possibility of allotransplant may be appropriate.

DR LOVE: So would it be similar to how they’d manage a patient with 17p for example, or p53, away from chemoimmunotherapy for example?

DR BARR: Yeah, I think so. I honestly think most of the considerations that you would think of for patients with deletion 17p really apply to complex karyotype, as well. So they’re very similar, in my mind.

DR LOVE: So another question, can you talk a little bit about second cancers that are seen in people with CLL? How often you see it? What kind of cancers? And whether there’s any evidence that any of the therapies increase the risk.

DR BARR: Sure. So it was recognized a long time ago that there is a higher risk of cancers overall, but as the years have gone by there have been a number of analyses that showed not only are there higher rates of the common cancers, but there’s a very high risk of skin cancers in our patients. And so as a result recommending dermatologic evaluation I think is critical. And we actually have a dermatologist working with us in clinic who can see patients in the same room/same day if appropriate.

So it is a risk. We otherwise recommend the standard screening evaluations that they often get through their primary care physician, but not necessarily screening more aggressively because of the lack of the data recommending we do so.

We think chemoimmunotherapy does increase this risk, and FCR’s the best example of there certainly is an increased risk of secondary myeloid neoplasms. There doesn’t seem to be a higher risk with the novel agents, acknowledging that we don’t have the same length of follow up as we do with chemotherapy.

Up-Front Management of CLL in Patients Who Are Older or Have Comorbidities — Stephan Stilgenbauer, MD

DR STILGENBAUER: So, welcome to this lecture on the Upfront management of CLL in patients who are older or have comorbidities.

Now this slide summarizes the path from the biology to therapy in CLL, and provides us with the new treatment options that we have available today for our patients.

So, when we walk through this clockwise, from the left lower corner, we see that in the past we had DNA damaging chemotherapy only as a treatment option. Now over the years, antibodies have been developed, mostly targeting CD20, such rituximab, ofatumumab and obinutuzumab. And more importantly, over the recent years, other factors of CLL biology have been discovered that provide great treatment targets today.

One of these elements is the B-cell receptor signaling pathway and agents such as ibrutinib and acalabrutinib targeting BTK have clearly revolutionized CLL treatment.

Idelalisib and duvelisib are agents that have been licensed for treatment focusing on PI3K, but that have fallen out of favor a bit more due to their toxicity profile.

Cell-based therapies, CARs, under development, also for treatment of CLL patients. And last but not least, the newest kid on the block is venetoclax, an agent focusing on the apoptosis machinery that is dysregulated in CLL and that is specifically targeting Bcl-2.

In the next few slides, I would like to highlight a few studies that have led to the licensing of these agents for the treatment of CLL patients.

Now, the first study we want to look at is the CLL14 trial, a trial for untreated elderly or unfit patients with CLL, and this trial randomized patients in need of treatment 1:1 to either chlorambucil plus obinutuzumab or venetoclax plus obinutuzumab.

The median age of the patients enrolled on this trial was 72 years. The SEER score was high, and the renal function was impaired. So this was clearly a typical elderly CLL patient population.

This was an international, Phase III trial in 196 centers in 21 countries. Obinutuzumab was given in both arms at the usual 6-cycle regimen, and chlorambucil was given for a 12-cycle treatment duration as was venetoclax after the usual ramp up. So in both arms we have fixed duration treatment for 12 cycles here.

This slide is looking at the clinical response and you see that this is significantly higher with venetoclax-based therapy, with a remarkable complete response rate of 49.5%.

The next slide is looking at the MRD response and the time course of MRD. In the right panel, you see the chlorambucil treatment; in the left panel venetoclax-based. Already with chlorambucil and obinutuzumab, we achieve MRD negativity as indicated in the green bars, but this is much more pronounced and much more durable when you focus on the venetoclax-based therapy.

Now these are the adverse events observed in this trial for both treatment arms and comparing the time during treatment and the time after treatment. You see that the leading high-grade toxicities are neutropenia, thrombocytopenia and anemia, with a little more pronounced neutropenia rate with venetoclax-based therapy. But, fortunately so, this does not translate into a high rate of febrile neutropenia in both treatment arms.

Tumor lysis syndrome is not an issue with the usual precautions of prophylactic measures and laboratory monitoring. And the little indications that we have to follow with a longer follow up, probably will all new agents, are the secondary neoplasms that appear numerically a bit higher in the venetoclax arm here. An important point is here again the comparison of the AE events during treatment and after treatment. And you see that after treatment, clearly the numbers go down very much lending support to the concept of time limited therapy.

Now this is the primary endpoint of the trial, progression-free survival, and here we clearly see a significantly superior outcome with venetoclax-based therapy indicated in the blue curve. The 3-year PFS rate with venetoclax treatment is 82% and clinically meaningful, superior, as compared to chlorambucil-based treatment.

Now this slide is looking at important biomarkers and here’s the IGHV mutational status brought into play. In red, you see the patients treated with chlorambucil-based treatment, the dotted red line, patients with unmutated IGHV status. In blue, you see the patients treated with venetoclax-based therapy, again dotted blue line unmutated status.

When you compare the curves you clearly see that in particular the patients with unmutated IGHV status, or the 2 dotted lines, benefit particularly from venetoclax-based therapy. But also, within venetoclax-based therapy, IGHV mutation status with longer follow-up appears to matter a bit, with a very good outcome for patients with mutated IGHV status of the solid blue line as compared to the dotted blue line.

Now the next slide is looking at similar cartoon, now broken down not only by treatment but also by 17p and TP53 mutational status. A similar picture emerges, both red lines, chlorambucil-based treatment; both blue lines, venetoclax-based treatment; solid lines, patients with a 17p deletion and/or TP53 mutation, and broken lines without this abnormality.

You see the worse outcome obviously have patients on chlorambucil-based treatment with 17p deletion and/or TP53 mutation. And outcome with venetoclax-based therapy is also somewhat affected by 17p and TP53 mutation status, with the solid blue line having a somewhat inferior outcome as compared to patients without this abnormality.

However, at 24 months, we see that the PFS comes to lie at about 70%, something that we can memorize when we compare this to other treatment options in later slides.

Now, this is looking at another biological phenomenon of CLL, namely the complex karyotype. And here outcomes compared for chlorambucil and venetoclax, again based on presence or absence of a complex karyotype. You see that the patients with a complex karyotype, indicated in the blue curves in this analysis, appear to particularly benefit again from venetoclax-based therapy and have much better outcome with that treatment as compared to chlorambucil.

Now, this brings us to the next important big treatment principle, namely agents targeting B-cell receptor signaling. And here we have ibrutinib and acalabrutinib license targeting BTK, and idelalisib and duvelisib targeting PI3K.

The later 2 I don’t want to go into deeper because they play rarely a role in our treatment armamentarium today and certainly not in the frontline treatment setting for unfit patients.

Now an important trial coming to ibrutinib is the ILLUMINATE study, again a study for untreated elderly, unfit CLL patients. And this trial, a 1:1 randomization, was done between chlorambucil plus obinutuzumab, given for 6 cycles, so it was somewhat shorter treatment duration as compared to the CLL 14 trial, as I’ve shown you before, ss compared to ibrutinib plus obinutuzumab, obinutuzumab given again for 6 cycles and ibrutinib continuous therapy.

This table is looking at the adverse event profile of both treatment arms, broken down into the first 6 months on treatment and then full AE period. And of note, the full AE period is much longer on ibrutinib continuous therapy than as compared to chlorambucil fixed duration treatment.

When you scroll the list of high grade adverse events, here, again, hematologic toxicity is leading. Neutropenia is highest upon the list, followed by thrombocytopenia. Then there’s pneumonia. Atrial fibrillation that we have learned of as specific side effect of BTK inhibitor treatment and other things such as hypertension and infusion-related reactions that obviously are observed with antibody treatment.

Now when you compare the first 6 months on ibrutinib therapy and the full AE period, you see that adverse events accumulate over time. For instance, neutropenia becomes more common as does pneumonia or other things, such as hypertension. And, therefore, clearly, we have an indication here that with longer treatment duration side effects in patients appear to accumulate.

This is the primary endpoint of the ILLUMINATE study, progression-free survival comparing the 2 arms with median follow-up of 31.3 months. We have a statistically significant and I think clinically very meaningful benefit of ibrutinib-based therapy as compared to the chlorambucil treatment arm.

This brings us to the next important ibrutinib-based study, this is the ALLIANCE trial, again for untreated elderly patients with CLL. Patients were enrolled here solely based on age being –- at an age of 65 years or older. And this was a 3-arm randomized trial with bendamustine plus rituximab as the standard arm given for 6 cycles, compared to ibrutinib monotherapy as continuous treatment, and, as a third arm, ibrutinib combined with rituximab given again for the usual 6 cycles and ibrutinib as continuous therapy.

Now this is looking at the response from the 3 treatment arms. You see that response overall is higher with ibrutinib-based therapy, but the proportion of patients who achieve a CR is relatively small.

This brings us to the adverse events from this trial. Again, a table comparing the 3 arms and the Grade 3 and higher adverse events for the time on treatment plus 30 days after that. And of note again, the median time on treatment is 6 months only for the BR arm and was 32 months here for both ibrutinib treatment arms.

Hematologic toxicity is higher with bendamustine/rituximab, in particular neutropenia. But non-hematologic toxicity is higher with ibrutinib-based therapy. Fortunately, so, febrile neutropenia is relatively rare in both treatment arms, a little higher with bendamustine/rituximab. But infections, overall, occur at a considerable proportion of patients and again appear to be a bit higher, possibly due to the longer AE capture period with ibrutinib-based treatment.

Hypertension, at the very bottom of this table, appears also to increase over time and is accumulating here at a relatively high incidence. And again, atrial fibrillation is observed as a relatively specific side effect of BTK inhibitor-based therapy.

This looks at the primary endpoint of the ALLIANCE study, progression-free survival. And you see that both ibrutinib treatment arms, given in red and blue here, are statistically superior as compared to the BR treatment, given in the black curve.

On the other hand, you see that with regard to progression-free survival, the addition of rituximab, so the IR regimen, does not appear to be beneficial. Outcome is very similar if ibrutinib is given alone or combined with rituximab in this trial.

The next slide again looks at an interesting subgroup analysis. These are the patients who have a mutated IGHV status, so the prognostically favorable subgroup of patients. And here you see that the benefit is much less pronounced and appears to become obvious only with longer follow-up, so in these patients the benefit of ibrutinib-based therapy is less marked.

The next slide looks again at the subgroup of patients with a 17p deletion. And here, you see in the solid black curve that patients with a 17p deletion when treated with bendamustine plus rituximab have a dismal outcome. But, also, among the patients treated with ibrutinib or ibrutinib plus rituximab, so the red and blue curves, you see in the solid lines that the patients with a 17p abnormality appear to fare a bit worse as compared to patients without these abnormalities. Again at 24 months the curves come to lie at about 70%, very similar to the venetoclax-based treatment that we have observed before. Longer follow-up you see, clearly needed to cull out more marked differences.

Now the next study I would like to focus on is focusing on the second generation BTK inhibitor acalabrutinib. This was the ELEVATE-TN trial, again for untreated elderly patients with CLL. Key inclusion criteria here were again an age of 65 and older, or among patients less than 65 years old if they had relevant comorbidity or decreased renal function.

This was a 3-arm randomized trial comparing again chlorambucil plus obinutuzumab as a standard arm. Here again, given for 6 cycles only, compared to acalabrutinib monotherapy and acalabrutinib plus obinutuzumab, again obinutuzumab given for 6 cycles and acalabrutinib as continuous therapy.

This slide looks at the adverse event profile of the 3 arms, here given for any grade toxicity and Grade 3 and higher toxicity. You see at the very top of the table that here we see a new adverse event that is rather specific for acalabrutinib, namely headache. This is usually of low grade and transient and goes away when just continued on therapy. But this is something new that we have to focus on. You see again, diarrhea at the top of the list as a class effect of all BTK inhibitors. And then hematologic toxicity such as neutropenia, bleeding events, contusion, arthralgias, again, as a BTK inhibitor specific event, and so on.

Fortunately, when you focus on the second column of each treatment, the Grade 3 and higher toxicities, numbers become very small. Of note, in the acalabrutinib/obinutuzumab arm neutropenia appears to be increased, probably due to the addition of the antibody. But fortunately so, the infectious complications appear not to increase very much.

The next slide looks at the primary endpoint again of the trial. This is progression-free survival comparing the 3 treatment arms. Both acalabrutinib arms, given in purple and blue here, improved progression-free survival significantly as compared to the chlorambucil treatment, given in the green curve. And, although the trial was not designed to detect this difference, the addition of obinutuzumab, interestingly, appears to further increase the progression-free survival when you compare the blue curve, acalabrutinib plus obinutuzumab, as compared to the purple curve, acalabrutinib alone.

The next slide again looks at the important subgroup of patients with a 17p deletion. In red you see the chlorambucil-based therapy, where, in the solid red line, you see that patients with a 17p deletion have the worst outcome. But, although follow-up is rather limited here in this analysis, it appears that the solid blue and the solid gray line, patients with a 17p deletion with acalabrutinib-based therapy, again appear to fare a bit worse. And when you look at the 24-month landmark, it, again, appears that progression-free survival comes to lie at about 70% in this comparison.

Now, this brings us to the end and to the conclusions of this lecture regarding the Upfront management of CLL in patients who are older or who have comorbidities.

So there’s clearly improvement with targeted therapy, for instance, venetoclax plus obinutuzumab or ibrutinib or acalabrutinib with or without CD20 antibody, when compared to classical chemoimmunotherapy. PFS appears to be similar for all targeted agents that have been introduced into the CLL treatment armamentarium in across-trial comparisons, and we obviously need head-to-head comparisons of the novel agents to derive meaningful conclusions.

The benefit appears to be most pronounced in CLL patients who have unmutated IGHV genes, so the unfavorable subgroup, with chemoimmunotherapy.

Of note, outcome of patients with a 17p deletion and/or TP53 mutation appears to be still inferior with all targeted therapy as compared to patients without these abnormalities. But the outcome of this patient group is much improved when compared to chemoimmunotherapy.

The choice of either Bcl-2 inhibitor or BTK targeting agent as frontline treatment for our patients, therefore, is largely based on tolerability issues, and these may be focusing on patient preference with regard to treatment duration and treatment monitoring. They may be focused on co-existing conditions, such as hypertension, cardiovascular or renal disease. And they may be focused on concomitant medication such as anti-coagulates and antiplatelets or drug-drug interactions in particular in this patient group of elderly patients with comorbidities.

This brings us to the end with a favorable outlook. I think we can say that we have made dramatic progress in particular for elderly patients with comorbidities because these patients benefit to a great degree from the novel treatment options that we have available targeting Bcl-2 and targeting BTK.

Thank you very much.

DR LOVE: That was really terrific.

Just a couple of questions and follow up.

I realize, for example, how effective obinutuzumab is at clearing the blood, say before you give venetoclax. Right. So, for example, in an attempt to, let’s say decrease the white count, lower the risk when they get the venetoclax, is it clinically a big difference when you use — I don’t know even know — when you compare obinutuzumab to rituximab in like, clearing the blood?

DR STILGENBAUER: Yes, it is. It is. It's much more brisk. Much more rapid. Much deeper in response. It is a very interesting concept to kind of debulk the patient with obinutuzumab and then come in with the venetoclax. On the other hand, you buy the infusion-related reaction with that concept. Which, with obinutuzumab, sometimes is also challenging. But I think over the years we have learned how to deal with that, how to manage patients when they have infusion-related reactions. And usually, it's limited to the first or maybe first and second dose only, and then you’re rid of it.

DR LOVE: Another question I had is roughly, what is the incidence of complex karyotype at diagnosis and then later on?

DR STILGENBAUER: Right. So at diagnosis or let’s say – maybe let’s better say at first-line treatment —

DR LOVE: Treatment. Yeah.

DR STILGENBAUER: — because we have more data there. It's 20 to 30% of our patients with CLL have complex karyotype defined as 3 or more abnormalities.

DR LOVE: Hmm. And do you approach those patients similar to 17p?

DR STILGENBAUER: That is very interesting. I showed the data from CLL14, from other clinical trials we have more limited data available because karyotyping is still very labor intense and a cumbersome technique because you need live cells. You need to set up culture. You need to do the chromosome banding and so on. So, we have limited data with the other treatment options. And 17p deletion largely overlaps with the group with a complex karyotype. So, it's a difficult analysis to cull down the individual effect of 17p alone versus complex karyotype alone because they overlap.

In essence, I think, yes, we, today view complex karyotype as similarly adverse as we do with 17p deletion.

DR LOVE: Hmm. Another question I have is the issue of efficacy of venetoclax-based therapy versus BTK in 17p. I think at this point it's indirect comparison. Do you have any sense about how the two strategies compare? And do you have any preference in terms of treatment?

DR STILGENBAUER: Right. So, we have limited data available. And frequently held, I would say belief, is that BTK inhibitor is better, more efficacious and more durable with regard to outcome in patients with a 17p deletion.

I tried to illustrate it in my slides, that the evidence for that is rather limited. All of these curves come to lie at about 70% at 2 years PFS.

The point that I think that you have to take into account is that BTK inhibitor is continuous therapy. So these patients fail if they progress on continuous therapy, while, on venetoclax, after 12 months fixed duration treatment, most of these patients fail later and have the option actually of retreatment with venetoclax.

So the more fair comparison would actually be PFS1 with a BTK inhibitor, versus PFS2 after repeat treatment with venetoclax.

So, to me, there’s clearly no proof that continuous BTK inhibitor therapy is better for those patients as compared to a Bcl-2 inhibitor.

DR LOVE: Do you ever consider continuing venetoclax in these patients instead of stopping it?

DR STILGENBAUER: That's an interesting point. We have data from MURANO, so in relapsed/refractory CLL, where, after 2 years fixed duration venetoclax as you know, the MRD kinetics were looked at for those patients who, at the end of this 2-year fixed duration treatment, had high MRD levels already again. And when looking at the kinetics, these patients were actually rising with their MRD level already during venetoclax-based therapy. So this kind of argues against that concept of continuing because these patients apparently developed resistance already on venetoclax. And to me, conceptually, the whole principle of this deep response with venetoclax combined with an antibody is that you have to aim at fixed duration, time limited therapy with this treatment principle.

So let me just bring up a couple of scenarios that we hear a lot and one is the older patient, of course, the patient in their eighties. The patient with prior history of hypertension. Maybe some cardiovascular disease. Chronic renal disease. When you think about those kind of patients who require treatment, how do you sort out the two main roads to travel, so to speak, or how do you sort out options with those kind of patients?

DR STILGENBAUER: So, clearly, the elderly population with comorbidities is the challenge that we have. Because despite the dramatic progress with BTK inhibitors and Bcl-2 inhibitors, both classes of agents have their downsides, one is the cardiovascular disease with atrial fibrillation or other arrythmias possibly become an issue. The increase of hypertension with BTK inhibitors, in particular on long-term continuous therapy is an issue. Bleeding events in particular when anti-coagulation is required is becoming worse.

On the other hand, with venetoclax we have an issue with decreased renal function, in particular during treatment initiation. Usually, tolerability in the longer run then is very good.

So, I usually discuss these pros and cons with patients, for instance, are they happy to be admitted to the hospital for a few days to do the ramp-up safely and then continue as an outpatient? Or, are they happy to put up with a little bit of skin bleeding or so, no matter — but not be admitted to the hospital for the ramp-ups?

I think you can also describe the benefits of both treatments to patients. And then, most patients have a clear choice what they want to do, either continuous therapy because they feel safe then, or say, no, I don’t want continuous therapy. I just want fixed duration treatment and then be off that drug and enjoy long-term response. So this is kind of the way I think you can differentiate and tell patients, well, we have great options. And in the future, based on trials, we may have even combination treatments of these classes of agents licensed, probably in the near future already, that would be very beneficial.

Now with regard to choice of the BTK inhibitor. Obviously, already now licensed we have ibrutinib available and we have acalabrutinib available. We don’t have yet a head-to-head comparison that will guide our treatment much better. When we lay the trials side by side, it appears that there are some new things that we observed with acala, such as the headache, for instance, which can be a headache in daily practice.

On the other hand, things like off-target effects such as atrial fibrillation, also bleeding in some instances, appears to be a bit lower with acalabrutinib.

So, when laying the data side by side, it looks like acalabrutinib could be a bit better with regard to the classical ibrutinib side effects. On the other hand, we buy headache as a new adverse event that we have to handle.

Optimal Management of Adverse Events Associated with BTK and Bcl-2 Inhibitors — Matthew S Davids, MD, MMSc

DR DAVIDS: Well, thank you so much, Neil. It's really a pleasure to be able to talk about optimal management of adverse events associated with BTK and Bcl2 inhibitors.

So, we know that the BTK inhibitor ibrutinib has a well characterized and well-established toxicity. This is an important analysis that looked across 4 randomized control studies of ibrutinib, focused on the safety profile of this drug. And you can see on the right some of the most common Grade 3 or 4 adverse events with ibrutinib over time. The color codes there look at the timeframe when these AEs occurred, with the blue being early on within the first 3 months and then the different colors going down, up to 18 months or longer. And what you can see is that certainly cytopenias are common, particularly early on. These are often not due to ibrutinib but could be due to lingering effects of prior treatments and other factors such as CLL disease infiltration in the bone marrow.

But you can see that the incidence of other more serious toxicities is quite low, even things like atrial fibrillation, which is a known risk of BTK inhibitors, occurs fairly rarely in ibrutinib patients, about 6 to 8% of the patients have Grade 3 or higher atrial fibrillation. And at the bottom you can see that bleeding events are more common in patients on ibrutinib, as compared with the comparator arms of these randomized studies. And, although any grade bleeding events are quite common with ibrutinib, upwards of 40%, you can see that the rates of Grade 3/4 bleeding events are relatively low.

Now, one of the interesting things that's emerged from the US Cooperative Group studies recently is that we have 1 study looking at the older patients, this is Alliance, which is typically patients age 65 or older. And then you have the E1912 study, which is the ECOG study looking at patients age 70 years or younger. And actually, the toxicity profile in that second study, the ECOG study, actually looks a bit more favorable for ibrutinib as compared with the older patients. You can see the median age in that ECOG study is 57 years, compared to 71 years in the Alliance study. And you see dramatically lower rates of infection, about half of the rate of atrial fibrillation, less major bleeding, and a lot lower rates of hypertension.

Now, again, this is not a comparison here directly of younger and older patients, this is a cross-trial comparison. But I think it does certainly suggest that there may be some safety benefits in the younger patients who may tolerate this drug better.

Nonetheless, as ibrutinib is utilized in the so-called real-world setting, outside of clinical trials, we see that toxicity is really the most common reason for discontinuation. And you can see this here from a large series put together by Anthony Mato and colleagues, where they looked at the patients who discontinued either ibrutinib or the PI3 kinase inhibitor idelalisib. So focusing on the left column here, you can see that about half of the patients who stopped ibrutinib in this large real-world series did so due to toxicity. And this was much more common than stopping the drug due to CLL progression or Richter’s transformation or other issues.

So I think that even though the toxicity profile looks fairly favorable for ibrutinib in the trial setting, there have been more challenges in using this drug in the real-world setting and really keeping patients on drug long-term.

Now, one important study that has not received as much press, I wanted to bring it to everyone’s attention, is the CLL12 trial. This is a really important study because it's really one of the only ones right now that's looking at this space of higher risk CLL patients who are on watch and wait and utilizing an early intervention strategy to see if that's beneficial for patients.

This is a study largely being conducted in Germany and other countries in Europe and they’ve taken patients with early stage CLL that would not require therapy otherwise, and they’ve randomized them to early intervention with ibrutinib versus a placebo control. And you can see the AE profile for ibrutinib here, nearly everyone had a toxicity, 94.9%. About half of the toxicities here are Grade 3 or higher and you can see the list of different AEs leading to interruption, with arrythmias being fairly prominent at 18%, bleeding events at 8% and there were some fatal AEs on this study as well, although none of them were believed to be treatment related.

Now, one of the things that's really interesting about the study is that if you look in the placebo group, you see a numerically higher rate of AEs, 95.5%. So, to me, this really suggests that CLL patients have a number of issues going on medically. They’re complex medical patients. And that we can’t always necessarily blame the ibrutinib for the toxicities. And that's where I think it really depends what the specific toxicity is. Because if you look down at the rates of the AEs that led to interruption of placebo, you don’t see any dysrhythmias or just one major bleeding event, and so there are other events that are kind of random that led to discontinuation of placebo.

So, to me, this really speaks to the characteristic toxicity profile we see with BTK inhibitors like ibrutinib. We have to worry about cardiac arrythmias, major bleeding issues, and I think this CLL 12 study really nicely demonstrates that. And so far in this trial there’s been no overall survival benefit to early intervention with ibrutinib. So this is certainly a study that has not changed our practice right now. We still recommend observation, even for high risk CLL patients, like those with deletion 17p. And I think this does help inform our understanding of the safety profile of ibrutinib.

Now another question that we commonly get is should we be adding rituximab to ibrutinib, either in the frontline or relapse setting? And here’s some data from the frontline setting. This is from the Alliance study that I mentioned before where patients were randomized to either ibrutinib with or without rituximab versus a standard 6-month course of bendamustine and rituximab. And as you can see, there was no benefit in terms of the progression-free survival for adding rituximab to ibrutinib. But on the right side, you can see the toxicity profiles and there may be some additional toxicity that occurs in the patients who are receiving the rituximab. Certainly, we see some infusion reactions. We see a little bit higher rates of neutropenia, and obviously there’s the inconvenience of the infusions for patients.

So, without any significant efficacy benefit, even though there’s minor differences in the toxicity profile here, we generally do not recommend adding rituximab to ibrutinib.

I’ll say also that we have similar randomized data now in the relapse setting showing the same thing.

But things may be a little bit more complicated than that. I don't think we can necessarily extrapolate the data from ibrutinib to acalabrutinib, which is the more specific BTK inhibitor, now also approved for CLL, both in the frontline and the relapsed setting. And we also can’t extrapolate rituximab to the more potent CD20 antibody obinutuzumab.

This regimen of acalabrutinib with obinutuzumab has now been studied in this ELEVATE-TN trial. Patients were randomized in a 1:1:1 fashion to either acalabrutinib with or without obinutuzumab. And these were compared to the control arm of the standard 6-months of chlorambucil with obinutuzumab, and this is an older and frailer population. And, as you can see on the table on the right that you have some added toxicity with the obinutuzumab, any grade AEs are higher, but also you see higher rates of neutropenia. Of course, you can see infusion related reactions, although those rates were relatively low, because in this study they started with the acalabrutinib, which, interestingly, I think may mitigate some of those infusion reactions with obinutuzumab. You do see some higher rates of cytopenias, like thrombocytopenia and a bit higher rate of pneumonia as well with the obinutuzumab addition.

So, you do see some potential for a PFS benefit. You can see those curves between acala/obin and acala alone have separated a bit. This was not a study powered to look at that difference, but in a post hoc analysis there was a hazard ratio of 0.49 in favor of adding the antibody. So I think there may be some PFS benefit there by adding the antibody, but, on the other hand, there’s a cost in terms of the toxicities for the patient. As you can see, they are higher when you add that antibody.

DR LOVE: So, that's interesting. Did you say that the acalabrutinib, if you give it with obinutuzumab, reduces the infusion reaction?

DR DAVIDS: That seems to be the case. So, when we look at using BTK inhibitors, and this is probably true with ibrutinib as well, we’ve looked at this in the trial that we did with ibrutinib with obinutuzumab. What we think is happening is that there’s a mitigation of some of the cytokines and chemokines that lead to infusion reactions with obinutuzumab, CCL3, CCL4, there’s a long list of them. And those are exactly the same chemokines and cytokines that BTK inhibitors can decrease in CLL patients. So it may be very beneficial if you’re using a CD20 antibody, to start with the BTK inhibitor first.

DR LOVE: That's really interesting.

Do you see the same thing with ibrutinib?

DR DAVIDS: We do, actually. We do. We actually presented some randomized data at ASH last year from an investigator-initiated trial, where we varied the sequence of administration of the drugs and we found that the arm that had the highest rates of infusion reactions was starting with the obinutuzumab and only introducing the ibrutinib a month later.

DR LOVE: Wow. Another thing I was going to ask you about, as a general thought in patients who are having tolerability issues with BTK inhibitors, again I’m reflecting back on a bunch of cases I’ve heard about, what do you think about the strategy in a patient who’s really having a major problem of just doing, sort of a drug holiday? So, if the patient’s had a good response, they’ve been on it for a while, but now they’ve rash, whatever, arthralgias, something that's really a problem, rather than switching to something else, is it reasonable to just watch the patient for a while or are you going to lose something therapeutically?

DR DAVIDS: That's a great point, Neil, and you hit the nail on the head. They key is that the patient should be in a good response. So, if you have a patient early on who’s having some response to a BTK inhibitor and they’re having toxicity, it can be risky to stop the drug if you’re, for example, in the first few months because they still have a lot of CLL disease around, their disease could flare off the BTK inhibitor. But in the scenario that you pose, where a patient is already in a good remission, say they’ve been on ibrutinib for a year or 2, I usually can safely stop the drug for a period of time, sometimes even months, without progression of disease and that can provide an alternative to switching therapies.

DR LOVE: How about years?

DR DAVIDS: So there are some data from the ECOG 1912 study that patients can go a median of about 20 months after stopping ibrutinib due to toxicity before they have disease progression. And actually, some of those patients may not even need treatment again when they have disease progression right away until they meet the IWCLL criteria. So, yes, particularly in patients who have been on ibrutinib for a while, they can sometimes enjoy years of response off drug.

DR LOVE: You mentioned the trial looking at patients with adverse prognostic features treating early, even though wouldn’t meet the criteria. I had heard there was going to be a big Intergroup or US study looking at that. Is that the case?

DR DAVIDS: Yes, that's correct. The SWOG group is leading a trial that's just getting off the ground now with venetoclax plus obinutuzumab, looking at this as a time limited therapy as an early intervention strategy. So I think that's a very exciting study.

DR LOVE: You were mentioning that the other study didn’t show, I think it was progression-free survival benefit. But what do you think an appropriate endpoint is for a trial — do you think it should be survival? It seems like it takes so long to see.

DR DAVIDS: Yes, that's the challenge with these trials. So the German CLL12 study actually has looked at event-free survival as their primary endpoint, and, of course, they’ve demonstrated a profound event-free survival by using ibrutinib first because the patients who are on placebo are going to have events when they progress and then they’re going to be treated with drugs like ibrutinib. The problem is those patients could do just as well in the long-term if they’re treated later and, in fact, maybe they do better because they’ve had fewer cumulative toxicities.

So, unfortunately, I think we really are stuck with overall survival as the best endpoint for these trials. And, as you said, this is going to take many years to see in the CLL patients. So it's a challenging area to study.

DR LOVE: But when you think about it, this kind of reminds of, even of some of these adjuvant trials like the big osimertinib trial that was just reported with the disease-free survival advantage. I mean it's kind of a similar thought there. And there, they talk about, well, these people aren’t going to go through the experience of having brain mets and all these other terrible things that happen. When you look at the kind of events that occur here, from a quality-of-life point of view, could you make an argument that it's worth it? Or maybe not?

DR DAVIDS: I think it's a tough argument in CLL because these patients who are on observation often feel great. They’re often asymptomatic. And now you’re introducing a therapy like ibrutinib that has some real risks. There’s patients who have significant bleeding issues and atrial fibrillation. So it comes at a cost.

DR DAVIDS: So one of the questions in the field recently has been how immunosuppressive are drugs like ibrutinib and, for example, do we need to be doing pneumocystis prophylaxis in all of our patients? And so, there have been some cases of PJP pneumonia reported in patients on ibrutinib and we decided to look at our own center at the patients on BTK inhibitors and look at the incidence. Because at our center, like many, there’s no clear paradigm of being on or off PJP prophylaxis, it's really up to the individual doc.

So, when we looked at our 87 patients who were not on prophylaxis for PJP, but were on a BTK inhibitor, we only saw 3 patients who developed PJP. Granted the prevalence in the patients who were on prophylaxis was zero, so it does show that that PJP prophylaxis is effective. But the incidence rate is quite low for those patients not on prophylaxis, 1.9 per 100-person years, which is the number needed to treat of about 42 patients. So, from our dataset we kind of concluded there may be select patients who may be more immunosuppressed where you may want to think about it. But we don’t necessarily need to routinely be doing PJP prophylaxis for all of our ibrutinib treated patients.

Now, there also have been reports of invasive fungal infections with ibrutinib. And so, we looked at that in our dataset as well. We only saw 3 cases out of a couple of hundred of patients who were treated on ibrutinib or acalabrutinib. They were actually, all 3 cases were in the setting of combination studies, so the prevalence in the entire cohort was only about 1.4%, and for those patients on single-agent BTK inhibitors we saw zero fungal infections in 141 patients. So, we do think that this is a rare event, but it should be on the differential diagnosis for patients who have unexplained infection on BTK inhibitors.

So what about acalabrutinib, the more specific BTK inhibitor? Is this really a safer BTK inhibitor than ibrutinib? Well, obviously, we don’t have the head-to-head data yet, but we can kind of compare across the studies, and certainly there are some overlapping toxicities which are probably class effects of hitting BTK. So we see diarrhea that tends to be mild with both drugs. We also see mild bleeding and infections. There are some newer toxicities that we see with acalabrutinib that are less common with ibrutinib, in particular headache, which we see in up to 40% of patients on acalabrutinib. This does tend to be fairly transient when the patients first start the drug and responds to things like caffeine and NSAIDs.

You do tend to see, at least numerically, lower rates of atrial fibrillation, possibly major hemorrhage, less skin toxicity and possibly less pneumonitis, at least as we compare across studies with acalabrutinib compared to ibrutinib. And we have seen reports over the last few years of ventricular arrythmias reported on ibrutinib, even some cases of sudden cardiac death. We don’t know for sure that these are directly due to ibrutinib. The numbers are very small. But I would say that these are not reports that we’ve seen yet with acalabrutinib, albeit with much smaller numbers of patients treated. But I do think that that's promising as we look forward with this drug.

So one question that often comes up is if we have patients on ibrutinib who are not tolerating it well due to various AEs, can we switch them to a more specific BTK inhibitor like acalabrutinib and still achieve response without recurrence of bad toxicity. And this is an important small subset of Phase I study of acalabrutinib, where patients were treated initially off study with ibrutinib for a median of nearly a year and then came off ibrutinib due to a specific toxicity that was protocol-defined and went on to acalabrutinib on this trial. And you can see in the pie graph on the right, that about 85% of the patients treated with acalabrutinib either did not have any recurrence of that toxicity that led to ibrutinib discontinuation, or perhaps it did reoccur, but it was at a lower grade.

And so, about 70% of these patients remained on acalabrutinib over a year and a half after making the switch, only 3 patients had to discontinue acalabrutinib due to AEs, and you can see that the median progression-free survival has not yet been reached, with a 1-year PFS of 83%.

So, to me, this really does suggest that it is a viable option to switch patients who are having ibrutinib intolerance to acalabrutinib. You can expect to continue to see a good response and hopefully with less toxicity. But I think that this is not a randomized setting yet in terms of the comparison of the 2 drugs. And I think that will also be important to understand the comparative toxicity.

So looking again across the different studies, you can see from the Phase III datasets, at the top, these top 5 rows are ibrutinib Phase III trials, the bottom 2 rows are acalabrutinib Phase III trials. And you see varying rates of the different toxicities. You tend to see lower rates of atrial fibrillation, as you see on the bottom there, in the 3- to 5% with the acalabrutinib studies. With the ibrutinib studies, generally 6- to 12%, although in that Alliance study with older patients you saw about 14- to 17% of the patients developing atrial fibrillation. And across the board, you can see subtle differences in the toxicity profiles. But I think this really again highlights the need for randomized data which, fortunately, we will have soon for this comparison.

Now we already have some comparative data that have recently emerged from the ASPEN trial comparing ibrutinib with a different more selective BTK inhibitor known as zanubrutinib. Zanubrutinib right now is only FDA-approved in relapsed mantle cell lymphoma, so not yet approved in Waldenström or in CLL, and this ASPEN study in Waldenström I think is nonetheless very interesting because, again, it's a randomized comparison of ibrutinib directly with zanubrutinib in about 100 patients in each arm. And if you look at all grade toxicity, you can see 18% of the ibrutinib treated patients experienced atrial fibrillation compared to 3% with zanubrutinib. The diarrhea rates were also lower with zanubrutinib, as were the rates of major hemorrhage, 5.9% versus 10.2%; lower rates of hypertension. And so, overall, a more favorable safety profile. They did notice more neutropenia in the patients treated with zanubrutinib, including Grade 3 or higher neutropenia. Not exactly clear what the mechanism is there. Interesting finding. But did not translate into higher rates of infection with zanubrutinib.

So I think this study is a good proof of principle, I included here in our CLL session because I think we probably will be able to extrapolate some of the safety data across B-cell malignancies, in terms of a more favorable safety profile for this next generation of BTK inhibitors compared with ibrutinib.

I would caution you against extrapolating any efficacy data across the different B-cell histologies because I think that could be very different. And I’ll just mention in this study there was no statistically significant efficacy benefit to the zanubrutinib.

And this is the trial I’ve alluded to a couple of times, the ELEVATE-R/R study comparing ibrutinib with acalabrutinib. This was targeted at patients with what was considered at the time to be high-risk CLL, which certainly includes deletion 17p. One of the interesting aspects of this trial is that it also includes patients with deletion 11q, who historically were high risk with chemoimmunotherapy-based regimens when this trial designed.

One of the reasons this trial is taking so long to read out is that we’ve since learned that patients with deletion 11q can do extremely well on BTK inhibitors, possibly even slightly better than patients without deletion 11q. So this is an event-driven study with a primary endpoint of progression-free survival comparing ibrutinib directly with acalabrutinib. And there just haven’t been enough events yet for the study to read out, but certainly we expect that soon.

I don't expect major differences in the PFS endpoint here, but you can see there’s a variety of key secondary endpoints focused on toxicity. And I think that's where we may see some real differences between these drugs, but certainly eager to see the actual data.

As we await those data, I’ll just mention briefly that we’ve been involved with a match adjusted analysis looking at acalabrutinib-based regimens, as compared with ibrutinib-based regimens across studies. So this has all the usual caveats of this type of retrospective research, but there were some statistical algorithms that were used here for matching the patient populations, to try to make these comparisons as effective as possible. And as we did this kind of comparison you can see on the left side acalabrutinib monotherapy versus ibrutinib monotherapy, that third column of rate difference. We did observe lower rates of infection, atrial fibrillation, a variety of toxicities as listed there.

And then comparing the combination of acalabrutinib with GA101, that's the other name for obinutuzumab, versus ibrutinib with obinutuzumab. Again, lower rates of other toxicities, including febrile neutropenia, edema. Higher rates of headache in the acalabrutinib-containing arm, as we expect. So, again, this is not a randomized comparison here, but maybe some helpful information as we await those randomized data.

DR LOVE: I didn’t see that. Is that the first time you’ve presented that?

DR DAVIDS: Yes, this was presented at the EHA meeting this summer, so pretty recent presentation

DR LOVE: Super cool. Can you comment on the issue of arthralgias, and also skin issues?

DR DAVIDS: So, ibrutinib is a drug that targets many different kinases, and one of them interestingly is EGFR, which you’re very familiar with Neil from other malignancies, and I’m sure, as you know, rash is common with EGFR inhibitors. So, we do tend to see rash fairly commonly with ibrutinib. Seems to be less common with the more specific BTK inhibitors, which don't target EGFR. I think arthralgias, the mechanism is less well understood. But certainly, I can say from experience treating patients with both drugs, I tend to see lower rates of acalabrutinib-related arthritis or arthralgias compared to ibrutinib. So that does seem to be another potential advantage of the drug.

DR LOVE: Again, we had a case recently where a doc felt like acalabrutinib was getting sinus tachycardia. Has that been reported?

DR DAVIDS: You do see some supraventricular issues in terms of tachyarrhythmias with acalabrutinib. So, some of that probably is a BTK class effect, but the rates of that seem to be lower than with ibrutinib.

DR LOVE: Another question is there are trials now looking at combinations of venetoclax plus BTK inhibitors, sometimes with anti-CD20. How do those mix in terms of tolerability?

DR DAVIDS: They seem to be well tolerated. So we have the most mature data now for ibrutinib plus venetoclax combinations. There’s a number of studies, now both in the frontline and the relapse setting. And in general, the toxicity profiles are fairly non-overlapping. Both drugs can cause diarrhea, so you tend to see fairly high rates of mild diarrhea. You can also see neutropenia and some infections, probably at higher rates than when you use either drug on their own.

We’ve also looked at combinations with triplets, and there’s been data published recently on the ibrutinib/venetoclax/obinutuzumab triplet. We presented our data on acalabrutinib/venetoclax/obinutuzumab. And now there’s data on zanubrutinib/venetoclax/obinutuzumab. So this is really, I think, the future of CLL, is exploring these doublet and triplet regimens. They’re not going to necessarily be required for all patients, some patients may do well with monotherapy. But for certain patients, particularly higher risk patients and those who are younger and fit, these combinations may allow for time-limited therapy with excellent tolerability.

DR LOVE: I want to ask you another generic question, which is, when you’re switching between a BTK and venetoclax, it could be, as you were talking about, because of progression or it could be because of the tolerability issues. How do you handle that transition? And do you handle it differently in a patient progressing? I’ve heard people talking about keeping the BTK inhibitor going even though the patient is progressing. Is that what you do?

Obviously, you wouldn’t do that if they’re having tolerability. But what about that situation where you’re switching because of progression? Do you continue the BTK? And how come?

DR DAVIDS: Yes, so I certainly do. And that's one of the lessons we learned the hard way early in the development of ibrutinib. We didn’t understand that. And so, as you know, often when we have a patient progressing on a cancer therapy, we stop it in anticipation of the starting the next therapy. And we found when we did that, with ibrutinib even for a few days, patients could have massive disease flares of their CLL that made it very hard to control, particularly with a drug like venetoclax where you’re starting at a very low dose of 20 mg for week, and then 50 mg, and it takes a few weeks until you get up to a therapeutic dose.

So, certainly at a minimum, I would recommend continuing the BTK inhibitor right up until the day before starting venetoclax. If you feel comfortable doing it, which I do now given all the combination data we have, I’ll actually often overlap the ibrutinib for the first couple of weeks when you’re at those lower doses of venetoclax at 20 and 50mg, and then only stop it once we’re up to a 100 mg. Be mindful that there is a drug/drug interaction between ibrutinib and venetoclax. And so, you are actually seeing effectively higher concentrations of the venetoclax when you’re using ibrutinib, probably about 50% higher drug exposure there. So you do need to monitor closely for tumor lysis syndrome if you’re doing that type of doublet therapy.

DR LOVE: Interesting.

DR DAVIDS: So let’s change gears a little bit and talk about the AE profile for the Bcl-2 selective inhibitor venetoclax. So, these are some data to review from the first-in-human study, where we found that venetoclax was generally well tolerated, but we did notice some specific toxicities. I think most are probably familiar with the last one listed in the table here which is tumor lysis syndrome, which occurred typically early in the course of this study when we were still working out the right starting dose and the right ramp-up scheme. So there were 3 cases of clinical TLS on this study, including a patient death due to TLS, which required us to really manage the patients closely, do this dose ramp-up week by week, and by doing that we’ve been able to show that it's safe to start this drug.

Now you can see other toxicities that are listed here that are common, including neutropenia, which occurred Grade 3/4 in about 40% of patients. Diarrhea in about half of patients, but this was almost entirely Grade 1/2. And you can see a variety of other toxicities listed here.

I’ll note also that even though neutropenia is quite common, febrile neutropenia is rare, only 6% of patients on this study developed febrile neutropenia, despite the fact that this was a heavily pretreated population of CLL patients.

So, toward the end of the early phase of venetoclax development, when we had several studies completed, I led an effort to do a comprehensive safety analysis across the portfolio of early venetoclax trials in CLL. And this looked at about 350 patients treated with venetoclax monotherapy. And you can see the color-coding here represents different cytopenias on the left, neutropenia in green, anemia in blue, and thrombocytopenia in the orange. And the different days here represent days from starting venetoclax.

So you can see the first onset of Grade 3 or 4 cytopenias, as well as the prevalence, is highest in that first month starting on venetoclax. But as you get out toward the end of the first year, the rates of Grade 3/4 cytopenias go way down and this drug is very well tolerated there.

On the right side you can see kind of a similar analysis with gastrointestinal side effects, diarrhea, nausea/vomiting. You do tend to see them in very mild form initially when patients are starting on venetoclax. But usually these go away within the first few weeks.

Now as we looked across the 166 patients from this dataset who were treated with the currently approved dosing ramp-up for venetoclax, there were only 2 patients who had laboratory changes consistent with tumor lysis syndrome, but these were effectively managed and none of these patients had clinical sequelae of TLS.

Now in the Phase III experience, we’re looking at multicenter studies across the world and you do tend to see some TLS here, particularly in this MURANO study. MURANO study started with venetoclax and then added in the rituximab and you did see a 3% rate of tumor lysis syndrome, although only 1 case of clinical TLS; this was mostly just laboratory changes that were manageable.

Interestingly, in the CLL14 study, this is the frontline study, the design of the regimen is to start with the obinutuzumab for about 3 weeks and then to introduce the venetoclax. And it turns out that this very effectively cytoreduces the patients and lowers the risk of TLS from venetoclax. And, in fact, the 3 cases of laboratory TLS that were observed on this CLL14 study were actually all in patients treated with obinutuzumab, which also had some low risk of TLS. So there was no TLS occurred in patients who were starting venetoclax on this study.

So how can we put this together to think about the risk of TLS now in our CLL patients starting venetoclax? So the label in the US divides patients up between low tumor burden, medium tumor burden and high tumor burden as you see at the top here. And this was based on lymph node size and absolute lymphocyte count.

We do need to be mindful, also, of renal function. We know that creatinine clearance of less than 80 mL per minute increases the risk of TLS, and this is going to be really most of our patients who are often elderly with CLL who are going to have this increased risk due to renal function. And remember that in most of the venetoclax trials early on, you had to have a creatinine clearance of at least 50 to get on venetoclax. Some of the later studies have relaxed that a bit, so we do have safety data now down to 30 mL per minute of creatinine clearance.

Obviously, we have to keep in mind other medical comorbidities, and this can really help us to establish the TLS risk. I pulled this from the European label, just because I find it to be helpful. As we think about establishing TLS risk, at the bottom, I think it's useful to think of all of our CLL patients at being at-risk for TLS, but there are some patients who are at greater risk. And I like this kind of dichotomy rather than saying there’s low risk or high risk. I think everyone has some risk, but we use these mitigating factors here to understand who’s at the greater risk.

So this is the approved ramp-up scheme that you’re probably familiar with. We start with 20 mg and go up week by week to 400 mg. Obviously, I mentioned, when you’re using a CD20 antibody, you should be following what was done in the trial, with MURANO using the venetoclax first, with CLL14 using the obinutuzumab first. And again, by doing this and following the FDA label closely, this is a safe way to introduce venetoclax to the patient.

Here’s some tips in terms of TLS prophylaxis and monitoring for venetoclax patients. I always ask my patients to start drinking water a day or 2 before, just oral hydration, to get a good baseline. We can give intravenous fluids the day the patients come in if they really need to be boosted up. Patients should also start on an antihyperuricemic agent a couple of days before, particularly allopurinol is what we use most commonly. And then they do need close lab monitoring, particularly those first 2 doses, 20 mg and 50 mg.

We try to get an early lab check the day they come in pre-dose. Sometimes we could do that check the day before if that's easier logistically. Really, the key is to get them started early in the morning the day that they're starting. If you can start them by 8:00 or 9:00 in the morning, then you can do labs 6 to 8 hours later, hopefully before your clinic closes, and get those results back to understand that the patient is safe to go home. We also do 24-hour labs for those first 2 doses to make sure there’s no evidence of TLS there.

I think really, on the right side, you can see emphasizing evaluating blood chemistries in real time is really crucial. You can’t send off a uric acid that comes back 2 days later for these patients. So if you don’t have the ability to get rapid return of labs, then it is best to admit these patients to the hospital for initial dosing. And similarly, if you have high-risk patients, greater risk, then you should also monitor those patients on the inpatient setting, at least for that 24-hour period. And if you don’t see any TLS at that point you can discharge the patient home.

So I wanted to take a step back and just talk about some of my general considerations and tips for toxicity management with novel agents in CLL. And this applies mostly to BTK inhibitors and the Bcl-2 inhibitor venetoclax, although I would say, in general, some of these principles may also apply to other novel agents like PI3 kinase inhibitors.

So the first thing is that, in general, when you have a patient who develops an active infection, I think it's generally best to hold the drug, at least until you’re seeing some signs of clinical improvement. Now one possible exception to this may be the COVID-19 situation, where we’ve talked a little bit about BTK inhibitors potentially having a protective effect against the inflammatory state in COVID-19. So that's a special case. But in general, if you have a bacterial infection or a pneumonia, I usually like to hold drug until the patients are headed in the right direction.

In general, if I have a toxicity that's requiring a drug hold, even something like atrial fibrillation, if I want to rechallenge the patient I’ll typically either start back at full dose or, if I’m starting back at a reduced dose, I’ll do that, but my goal is to get back to full dose. So, with ibrutinib, if they have AFib, I might stop the drug for a week, and when I restart it, maybe I start at 140. But I don’t leave them at 140 forever; I try to go up to 280 the next week and then back to 420, and many patients will actually tolerate that challenge.

Now this gets to the point that, Neil, you raised earlier about being hesitant to stop the drug soon after starting a novel agent. That's where we can run into difficulty with disease flare. And that's particularly true for patients who are progressing on novel agents.

But in general, on the flip side, I’m less concerned about stopping drugs in patients who’ve been on these novel agents for at least a few months, their CLL is in a good response, that's where you can be a little more liberal with stopping drug to allow toxicities to resolve and then rechallenging.

And then some final tips — we get a lot of questions about whether cytopenias are being caused by the novel agent, for example, we’ll see neutropenia in patients on ibrutinib. Is that being driven by the drug? Well, it certainly could be contributing. We generally find these patients can do very well by continuing drug. Sometimes we were seeing fluctuations in counts. We can support them with growth factor. So I generally think it's not the novel agent that's driving the cytopenias.

Now one clear exception to that is venetoclax and neutropenia. This is an on-target effect of the drug, that's why we see it so commonly with venetoclax. So, particularly for those patients, it's important to support them with growth factor support, typically if their ANC is dropping less than 1000, I’ll give them some pegfilgrastim. They don’t usually require it every 2 weeks; usually a single dose can send them off for a few months and they can do well. And you don’t need to stop the drug like you would with chemotherapy-based regimens, you can continue the novel agent and give the growth factor concomitantly.

And then this comes to Neil’s point from before, and I think it's an important one, that patients who have to permanently discontinue a novel agent don’t necessarily need to immediately start on new therapy if their reason for discontinuation was a toxicity. And this is particularly true for patients who have been on drug for quite some time.

DR LOVE: A couple of questions, you were talking about the ramp-up with venetoclax. And I have heard people talk about “accelerated” ramp-ups, bringing patients into the hospital, tertiary care situation, close monitoring and trying to do it faster. Patients are in rural areas where they prefer it, whatever. Any thoughts about that? Or any other variation? I know people love the package insert. But any thoughts about these other approaches?

DR DAVIDS: So, the first thing I would say is, unless you’re very experienced with venetoclax, I would recommend following the FDA label in general. But that being said, it is a long ramp-up period, 5 weeks, particularly for patients who are, for example, progressing post-BTK inhibitors, as we discussed. They can have very aggressive CLL and that could be detrimental to take so long to get up to the full dose.

So we and others, have been looking at this question. The group at Ohio State actually just recently published some data from a retrospective series at their single institution, that did show higher rates of laboratory TLS and even some cases of clinical TLS when patients were ramped up faster than the 5 weeks, although all of these patients ended up being manageable. And no one had very serious clinical sequelae.

So I think that's sort of a proof of principle that at least at a very experienced academic site that they can do it.

We’re actually presenting some data in a poster at this ASH meeting, looking at the multicenter experience retrospectively at a number of different sites across the US, again academic sites. And showing similar findings, we saw some increased risk of laboratory TLS compared to the trials, but, again, this was generally manageable. And we’re hoping that we’ll eventually have some prospective data looking at this question. But until we have that type of data, I would certainly advise people to be cautious about doing this. And in general, they should be following the FDA label.

DR LOVE: Another thing I want to ask you about. You mentioned COVID. And I’m curious what your thoughts are in terms of any of the CLL treatments, particularly the novel agents, and whether they increase or decrease, or what’s known about it, in terms of the risk of getting COVID, or complications from COVID? Also curious about something like FCR. I don’t know how many people are getting FCR nowadays, but I’m curious about that.

DR DAVIDS: So, we have some data on this now. We’re looking retrospectively from a large, mainly US-based collaboration as well as the ERIC group in Europe, which have now both published data on this. And it doesn’t seem like there’s any specific risk of a particular novel agent for CLL patients in terms of increasing the likelihood of developing COVID. I think we worry more about patients who are on certain therapies and their risks of developing worse COVID infection. And I think your point about chemoimmunotherapy, that's probably where we worry the most. That's obviously the most immunosuppressive of the regimens we use. But even actually the CD20 antibody is something that's a bit worrisome. And so, as we get into regimens like venetoclax/obinutuzumab, we worry a bit that the CD20 antibody may impair an immune response to COVID. And so, in the scenario where COVID is increasing in prevalence, if the pandemic is worsening again, that's where we are thinking more about some of the BTK inhibitor drugs as a nice alternative. But certainly we could still use venetoclax-based regimens when appropriate for our patients.

I’d say the other point that I worry about, as we move forward with COVID, is that, as we develop vaccines for COVID, we worry about patients who’ve been on recent CD20 antibodies, for example. Will they mount an appropriate antibody response to the vaccine? That may also be true in patients on BTK inhibitors. We just don’t know yet. So that's an area we really need to look at once we have the vaccine.

DR LOVE: Yeah, I just heard that mentioned as a concern. And yeah, I don’t know what we know about the effects of any of these therapies on vaccine reactions. Do we have any data? Or any theoretical thoughts?

DR DAVIDS: Unfortunately, we do have data in CLL for other vaccines, for example, pneumococcal vaccination tends to be less effective. There’s also a little bit of data about influenza vaccinations tends to be less effective for CLL patients compared to the general population. So, I think we do have some concerns about that for our CLL patients. I think the vaccines for COVID will be safe for CLL patients, but will they be as effective? I think probably not. I think we’ll have to rely to some degree on the fact that the rest of the population hopefully will be more immune, and they’ll be lower risk of transmitting it to CLL patients.

DR LOVE: Alright, so let’s hear about your cases. How about this 73-year-old man?

DR DAVIDS: So this is a 73-year-old patient of mine who has some hypertension and mild diabetes, diet controlled, and has CLL that's RAI Stage IV, with deletion 11q by FISH, unmutated IGHV. We did sequencing for TP53, which was normal, wild type. And this patient needs treatment. So very reasonable option to start on ibrutinib for this patient, but, unfortunately, about 10 weeks into the course he had developed some complications. So, although the disease was markedly reduced, the lymphadenopathy was less, the cytopenias had improved, the patient had developed atrial fibrillation.

Now in this particular case, the patient was actually asymptomatic. This was just picked up at a routine check at our office. The rate was not terrible, but it was in the low hundreds, so not really optimal in terms of rate control, so I decided to hold ibrutinib as an initial step here. And based on the CHA₂DS₂-VASc criteria, this patient did meet criteria for anticoagulation.

And so, the question became how to proceed optimally at this point for this patient?

DR LOVE: So, what were your thoughts in terms of what the alternatives might be? And what did you actually do?

DR DAVIDS: So, this is a patient where I was actually very encouraged by the response to ibrutinib. The lymphadenopathy really had melted away in just a matter of weeks. Cytopenias had also responded quickly. So I was enthusiastic about the idea of staying within the class of BTK inhibitors, but I was a bit nervous that the AFib had developed so early on in the course with ibrutinib, I worried about bleeding risks on ibrutinib and anticoagulation at the same time.

So I had a discussion with the patient about switching to acalabrutinib, or to moving on to something else like the venetoclax-based regimens. And this patient also liked the idea of the convenience of the BTK inhibitor, wasn’t interested in the venetoclax ramp-up at that point. And so, we actually switched this patient to acalabrutinib. And like the data from that study I showed where many patients who switched from ibrutinib to acalabrutinib were able to stay on acalabrutinib. This patient’s been on acalabrutinib now for several months without recurrence of the atrial fibrillation. So that's been very encouraging.

Now, unfortunately, the patient has still been on anticoagulation. I’d love to get him off anticoagulation. So, we’re in the process of doing an event monitor to see how frequently he may be in and out of AFib still. But if the patient’s really been out of AFib for a while, hopefully I can negotiate with the cardiologist to stop the anticoagulation.

DR LOVE: What kind of bleeding, if any, did the patient have on ibrutinib? And also, on acalabrutinib, any bruising, etc?

DR DAVIDS: Yes, the patient did have bruising on both drugs actually. Once the patient was on acalabrutinib he was also on the anticoagulation, so, there, it's a little hard to tell. But I do tend to see pretty similar minor bleeding rates with both drugs, ibrutinib or acalabrutinib. I think the differences in major bleeding events are small, if they’re there, but maybe favor acalabrutinib slightly.

DR LOVE: Interesting. So he had no cardiac history? Did he exercise? Was he in good condition?

DR DAVIDS: He wasn’t a major exerciser, kind of walking a couple of times a week. So he was in reasonably good condition, kind of in this gray zone of some risk factors, but no actual known cardiac disease, but with the diabetes that certainly made me a little bit nervous about leaving him in AFib on ibrutinib, for example.

DR LOVE: Okay, that's a great case. And we get a lot of questions about this. How about your second case?

DR DAVIDS: So, the second case is a fit 67-year-old woman with high-risk CLL, deletion 17p, that had previously had FCR — actually, at the time she had FCR she did not have deletion 17p. This is an example actually of clonal evolution that we can sometimes see in these patients who start out with low-risk disease, but particularly when they get chemoimmunotherapy can enrich for the high risk clone.

So, unfortunately, after just 2 years from FCR, this patient developed some bulky internal lymphadenopathy and very significant splenomegaly, which was starting to become symptomatic, 22 cm spleen.

So this patient started on venetoclax plus rituximab as per the MURANO regimen. Remember, this is the regimen that starts with the venetoclax ramp-up and then introduces the rituximab combination. And so, the patient was about, I guess 6 weeks or so into therapy totally, week 2 of the rituximab, and her ANC began to trend down significantly. Unclear if this was the venetoclax itself or maybe the addition of rituximab that caused this. The baseline wasn’t great to start with post-FCR, it was sort of around 1600, but the ANC went down to 950. Our patient was feeling well, was otherwise tolerating therapy well. She had a little bit of mild diarrhea from the venetoclax, but was afebrile, no signs of infection, despite the ANC less than 1000.

So, the question was how to proceed with this patient now?

DR LOVE: So, from your point of view, what do you think the reasonable alternatives were? And which one did you choose?

DR DAVIDS: So I get this question fairly frequently from folks who maybe don’t have as much venetoclax experience, and I tend to see that their inclination is to actually hold venetoclax and maybe even the rituximab. But this goes back to one of my principles, where remember, this is pretty early in the course for this patient. They’d just gotten up to the full dose of venetoclax They’re only on their second dose of rituximab. They have high-risk CLL.

So this is a patient I’d actually be quite nervous to hold the venetoclax on. Now, fortunately here, the neutropenia is quite mild. So I think there’s different options. One would be to just give growth factor and keep going at the same dose. Others might advocate for dose reducing the venetoclax. The nurse had asked me should we stop the rituximab — hold the rituximab maybe and continue the venetoclax? So you can see there’s a variety of different permutations here. But, again, going back to the characteristics of the patient, high risk patient, early in the course.

So what I did was continue the rituximab infusion, continue the venetoclax at full dose, and I gave a dose of pegfilgrastim. And this patient had an ANC that went back up into the high thousands; did fine. Came back the next week and the ANC was I think, 1900 or so. So that would be my approach here.

Now, a different scenario if this is a low-risk patient, if they’re later in their disease course and their disease is well controlled, then I think it's more reasonable to hold drug, think about dose reductions. But again, if you did reduce the dose of venetoclax in a patient like that, I wouldn’t encourage you to make that a permanent dose reduction. I would rechallenge the patient at a higher dose later.

We have some evidence from the Phase I study of venetoclax that patients treated long-term at 400 mg or higher, had a longer PFS than those patients treated at a dose less than 400 mg. Now granted, that's a retrospective comparison with post-hoc analysis within a prospective trial. But I do think that there’s some benefit to the higher doses of venetoclax in terms of durability.

Selection and Sequencing of Therapies for Relapsed/Refractory CLL — Kerry Rogers, MD

DR ROGERS: So, with the explosion of new treatments for CLL, the frontline treatment has taken a lot of, kind of the spotlight in terms of emerging treatments and what to do for treatment of CLL. And a lot of the conversation has been centered around that with the approval of both BTK inhibitors and venetoclax-based regimens. But I do think that treatment selection in relapsed/refractory CLL is still very important and that the conversation regarding what to do for refractory CLL has shifted as well.

Targeted agents are now very much preferred over chemoimmunotherapy for relapsed/refractory CLL because they have both better efficacy and in the majority of cases much better toxicity than chemoimmunotherapy. So, even though a lot of the conversation these days is around first-line therapy, I think this is still an extremely important conversation to have about relapsed/refractory treatment selection.

So, there’s really 3 categories of approved agents for relapsed/refractory CLL. One of them is the Bcl-2 inhibitor, so these are venetoclax-based regimens. Venetoclax has been studied both as continuous monotherapy and in a time-limited, 2-year treatment scheme in combination with 6 months of rituximab.

The next category of drugs is BTK inhibitors. And the two main agents that are approved are ibrutinib and acalabrutinib. And then there’s PI3 kinase inhibitors, idelalisib, which is given with rituximab, and also duvelisib.

So you’ll notice that these are all oral targeted agents that form the basis of these regimens and not chemoimmunotherapy.

The major questions we’re faced with then are which of these will be most effective for my patient in terms of disease control? And then, also, CLL is now in the fortunate spot where you can consider a side effect profile, so which of these agents have side effects that might go better with my patient’s individual existing health conditions? And, also, patient preferences regarding duration of treatment or visit schedule. And then lastly, a major question that is now starting to be answered, but I do believe it's sort of incompletely answered at this point is, does it matter what order you get these drugs in and how to sequence these drugs is extremely important. But we don’t have all the information about that yet.

So I’ve come up with a rough decision scheme for relapsed/refractory CLL, and again this is 2020 because there’s been so many new approvals in CLL and new drugs that I think this will probably change in the near future. But I kind of have this based on what therapy patients have received previously. So, for people who have previously received a BTK inhibitor or a PI3 kinase inhibitor, venetoclax has been specifically studied as a continuous monotherapy, so indefinite single-agent venetoclax. I do think, in some cases, it would be reasonable to give this in the scheme as per the MURANO study I’m about to discuss, but really, venetoclax-based regimens have been studied and are quite effective in this setting. And I don’t know of anything else that's approved that's as effective as venetoclax after either a BTK or a PI3 kinase inhibitor.

We do have some exciting clinical trials for this population, including reversible BTK inhibitors for those whose disease has become resistant to one of the approved BTK inhibitors. And then this is a population where, depending on the age and fitness and risk features of your patient, referral for either allogenic stem cell transplant or cellular therapy such as CAR T, which is investigational, should be strongly considered.

For people who received venetoclax previously, there’s now emerging data that BTK inhibitors can be quite effective provided they were not resistant to BTK inhibitors prior to receiving venetoclax. So I guess this should say people who received only prior venetoclax. So, if you’ve not received a BTK inhibitor previously, that would be that treatment of choice and there’s really the most data to support that at this time. I do think clinical trials should continue to be a strong consideration in this setting, referral for cellular therapy in appropriate patients. And then, there is a question about whether or not you can repeat venetoclax and there’s not a lot of evidence regarding this. But if you’ve done a time-limited venetoclax, I think it is a question whether you could do that kind of scheme again.

And then lastly, you’ve got the group of people that have not been exposed to either a BTK inhibitor or a PI3 kinase inhibitor which, of course, are in the same pathway, both B-cell receptor signaling antagonists or venetoclax. So, kind of non-targeted agent exposed in that regard. And for those, I do think it's a shared decision-making discussion with your patient regarding their preferences, regarding treatment, side effect profiles of these agents, risk category of their CLL, like whether or not they have high-risk features, and of course a clinical trial is always appropriate.

So, now that we’ve gone through this scheme, I’m going to show you a little bit of the data of the clinical trials that established how we think about relapsed/refractory CLL in this manner.

So, the MURANO study, which is really big news, this is the study that led to the approval of venetoclax and rituximab as a time-limited 2-year dosing scheme for relapsed/refractory CLL. So this was a Phase III study that compared the treatment plan you see in blue there, which is dose escalation of venetoclax, venetoclax with 6 months of rituximab, and then a 2-year scheme of venetoclax to bendamustine/rituximab given at what is really standard doses for CLL.

It was randomized, done internationally, and I think for this in particular, it's very important to note that there is a very high fraction of patients with deletion 17p who we all know do not respond well to chemoimmunotherapy and aren’t expected to. So keep that in mind when you look at the results of this study. And the fraction of patients that received prior chemotherapy as a prior treatment was very high, but exposure to B-cell receptor signaling antagonists, like ibrutinib or idelalisib, was actually quite low. So there you can see the study scheme. This was randomized. And the primary endpoint was investigator-assessed progression-free survival.

Four year follow-up was recently presented, so this is a rather long follow-up after a time limited regimen, so they had almost 2 years of follow-up for patients after they’ve completed treatment, because remember, it's 2 years of treatment in the venetoclax/rituximab arm. And you can see — of course, it was reported a couple of years ago that there’s a progression-free survival benefit to getting venetoclax and rituximab over the BR, and this is maintained. I wouldn’t have expected it's not to be maintained, but it's very nice that those curves separate and stay apart for progression-free survival. And there’s also an overall survival benefit to receiving the venetoclax-based regimen.

You can see the hazard ratios there below for both progression-free survival and overall survival at 4 years. So I think that this is extremely clear that patients should not be getting BR, they should be getting venetoclax and rituximab if those are the options. While the high fraction of patients with deletion 17p probably did affect the BR arm, I still think that this is a much better regimen. And it's very clear from this data that the venetoclax regimen is preferred.

So, moving on to BTK inhibitors, and I’m sure a lot of people are familiar by now with both ibrutinib and acalabrutinib. Both are irreversible BTK inhibitors and bind BTK and inhibit it at the exact same binding site. So, resistance to one of these means resistance to the other. So, a patient who progressed on ibrutinib should not switch to acalabrutinib. That's unlikely to be effective. And my colleague, Jennifer Wang presented at ASH last year some data looking at mutations and acalabrutinib patients develop the same mutations in BTK and PLCgamma2 as patients treated with ibrutinib.

So, these are not interchangeable in terms of resistance, but they do have differences in dosing scheme, with acalabrutinib being BID instead of daily and also in terms of side effect profile. Acalabrutinib is more selective and has fewer off-target effects, so has some — what appears to be some decrease in toxicities because it is more selective, not that you can’t have side effects from it but that's the advantage of acalabrutinib.

So, the Phase III study that led to the approval of acalabrutinib in relapsed/refractory CLL was called ASCEND. It was a very interesting Phase III study because instead of just comparing it to bendamustine/rituximab, it was compared to investigators choice of BR or idelalisib and rituximab, which I’ve abbreviated, IdR, there on the slide. So I think that's kind of neat that they allowed the choice between those two different options. And as you can see from the percents on the slide, the majority of investigator chose to give their patients the idelalisib regimen rather than chemoimmunotherapy.

So, I think when they were enrolling in this most people chose not to give their patient chemoimmunotherapy, so I think that's kind of an outstanding design in the trial to give people that option and not just compare it to BR. They can see what the study was stratified for, including deletion 17p.

And the results of this study, you can see the progression-free survival there, and there’s clearly a much better progression-free survival with the acalabrutinib compared to the standard therapy arm, which, again, was either idelalisib/rituximab or bendamustine/rituximab. You can see there, the 1-year progression-free survival and the hazard ratio clearly supporting that acalabrutinib is more effective in terms of progression.

And then here, actually, is what I think is kind of neat, which is a breakdown by the standard therapy arm. So more people got idelalisib than bendamustine, but you can see the curves there are very similar, and it doesn’t look like there’s a huge difference between the chemoimmunotherapy or idelalisib. Which, in my opinion, really makes idelalisib less attractive as relapsed/refractory therapy.

So, obviously, the study wasn’t initially designed to show a difference between BR and idelalisib/rituximab, but I do think it's very interesting to look at this progression-free survival curve in this manner.

And then here, of course, is overall survival. So, with the duration of follow-up that's been reported, there are not really differences in overall survival, but also there probably aren’t that many survival events. I do expect that this will potentially evolve over time, but as other agents such as BTK inhibitors that you can get commercially, are available, I think that would make a difference and also there was a crossover in the design, meaning that patients who were initially receiving BR, idelalisib/rituximab could go on to receive acalabrutinib. Which, at least in the patients that received BR is probably quite beneficial.

I think all these things really would lead to me not expecting a large survival benefit in this particular trial. So, I know that we all want to see an improvement in overall survival, but I think in this case the progression-free survival is sufficient to say that acalabrutinib is better and I don’t think it's a limitation that we did not see an overall survival benefit.

So, adverse events matter. And when we have highly effective therapies, I think what toxicities these patients are experiencing becomes a key deciding factor in what they’d like to do for treatment. So this is some of the adverse event data looking at acalabrutinib compared to the idelalisib or bendamustine-based treatment. You can see headaches, not Grade 3 or greater headaches, but headaches are very common with acalabrutinib and not really seen with the other treatments. And in my experience, this does seem to be a side effect that's rather specific to acalabrutinib. And also not something that usually impacts patients’ quality of life in most cases, but I do think that's an important thing to know about acalabrutinib.

And then if you can look at the neutropenia, especially the Grade 3 or greater neutropenia, it just appears to be numerically less in the acalabrutinib arm and higher than I would have thought in the idelalisib arm.

The other thing I really want to highlight here is the discontinuation rate for adverse events. So only 11% of patients had discontinued acalabrutinib for adverse events, but that was very high if you look at the idelalisib/rituximab regimen where you have almost half of patients discontinuing due to adverse events. So these PI3 kinase inhibitors, and particularly idelalisib, has some drug-related adverse events or toxicities that can frequently make it intolerable for patients. So that is not a very easy drug to take.

Grade 5 adverse events were similar between arms, which I think is helpful just to note that.

So there’s a couple of adverse events that were pulled out because they are of special interest and these are adverse events that are associated with the drug class BTK inhibitor. So you’d expect to see this in a drug that's a BTK inhibitor and the things that we first noticed with the ibrutinib experience.

One of them is bleeding adverse events. I’ve yet to see a full analysis of all the things that contribute to BTK inhibitors increasing bleeding. There’s some really interesting science there and I think it's probably more than one mechanism. But there’s definitely more, like Grade 1 or 2 bleeding with acalabrutinib, than you’re really seeing if you’re looking at percent-wise in the idelalisib or bendamustine arm.

And the other thing I want to point out is that cardiovascular-related adverse events, both atrial fibrillation and hypertension are not occurring at a very high frequency with acalabrutinib. And if you look at reported Phase III studies of ibrutinib, these occurred a much higher frequency.

So this really kind of begs the question, so if you have two BTK inhibitors, FDA-approved, on the market, being given to patients, some really important questions are is one of these more effective than the other? Remember, they have the same mechanism but that doesn’t necessarily mean they’re equally effective. And then also, I’m always personally invested in what the side effect profile is of these two drugs and which might be most appropriate for my patient, because I know I can offer any patient highly effective therapy. So you want to limit toxicity and take their preferences into account.

So this is a randomized, Phase III study, comparing ibrutinib to acalabrutinib at the standard dose. It is an ongoing study that is fully accrued, and the primary hypothesis is that acalabrutinib will be non-inferior in terms of progression-free survival.

I’m most interested actually, that this study will show us differences in adverse events between the two arms in a randomized fashion, and I expect to learn something about differences in frequency of things like atrial fibrillation and bleeding, as well as any difference in infections, which I wouldn’t necessary expect. So I’m must very excited to see that. I think that will help inform my clinical practice.

You can take a look there and see what it's stratified based on. But it is a higher risk CLL cohort, so you have to be previously treated and have either 17p or 11q.

With follow up with ibrutinib and acalabrutinib, actually, we’re not seeing those same kind of — in the relapsed/refractory setting, we’re not seeing that deletion 11q is really as adverse as it is in some other settings, like with chemoimmunotherapy. So, I think that's something in the study we have 11q considered high risk, but usually outcomes, at least in other reported studies with that cytogenetic feature, are quite good.

So, the reporting on this study is event-driven, meaning they have to have a requisite number of events before they will report it. So, while there is an estimated completion date of March 2021, I would love to know when we’ll actually get this data, and I’m not sure it's really going to be in March of 2021. I think it might take longer than that to get the data. So I’m looking forward to finding out the results of this any time now, but since it's event-driven, I think we’re all just going to have to be patient.

I personally don’t expect a large difference in efficacy between the two groups, I would find that a surprising finding if we were to see that. And I’m actually most interested in some of the adverse event data from this study.

So, lastly, I just wanted to put in a few words on the PI3 kinase inhibitors. So these also inhibit the cell receptor signaling, so both BTK and PI3K are in the B-cell receptor signaling pathway. These have been around for some time. So, idelalisib has been around in clinical use the longest and it is approved for use in combination with rituximab, or, actually, in SLL after two prior treatments. And then you have duvelisib, which is approved in relapsed/refractory CLL as a single agent.

There’s also umbralisib, and I’m very interested to see how umbralisib pans out. It is in some very exciting combination trials. And I’ve seen some initial results presented at meeting with that, that I think some of those regimens are going to be very exciting to offer our patients in the future depending on how their larger studies turn out.

In terms of the two approved agents, I think overall, they’re just not as effective as either BTK inhibitors or venetoclax. So if you look at the progression-free survival from the Phase III studies, particularly with duvelisib, you have a median progression-free survival of 13.3 months, which is not very good, particularly if you look back at some of those other studies I presented. It was not reached in the idelalisib study. But if you look at the data from the study, the efficacy just does not seem to be quite as good as these other agents that are available.

And then, my major concern with this class of drugs, too, is toxicity. As I pointed out earlier with idelalisib, there’s a very high discontinuation rate for toxicities. And people have a lot of trouble staying on these drugs long-term.

So I think both the adverse events and discontinuation rate for adverse events and the lesser efficacy compared to the other available agents, either BTK inhibitors or venetoclax, makes this less useful class of drug for my patients currently.

I do think that there are select patients that might benefit from this, such as patients that shouldn’t take venetoclax and shouldn’t take a BTK inhibitor, but aren’t resistant to them, I think the limited data available for use of this class of drug after BTK inhibitor shows they’re not really very effective. However, someone who couldn’t be in a clinical trial, that was resistant to ibrutinib or acalabrutinib and venetoclax, these might be worth trying. But, for me at least, I think the data doesn’t support them being a top tier choice for my CLL patients. Although, again, I am looking forward to seeing how umbralisib turns out, and some of their combination data may turn out to be exciting.

So, in terms of sequencing or what order to give these drugs in, especially with both BTK inhibitors and obinutuzumab and venetoclax being the frontline treatment choices now, this is going to become an increasingly interesting question is, what order do we give these drugs in.

There, I have shown data from a Phase II study that was looking at continuous venetoclax, single agent, after a B-cell receptor signaling antagonist. So, after either idelalisib or ibrutinib. And not all the patients in these studies were resistant; some had discontinued either the PI3 kinase inhibitor, BTK inhibitor, and then relapsed later. So it wasn’t 100% resistant patients. But if you look at the features I’ve listed there of these 2 separate cohorts, the cohorts were published either as ibrutinib as the most recent prior therapy or idelalisib as the most recent prior therapy. These are very high risk patients. So, median prior treatments were either 3 or 4. And actually, if you look, a good number of the most recent ibrutinib patients had received prior idelalisib and some of the most recent idelalisib patients had receive prior ibrutinib. So, this is a very adverse CLL population.

And I think the progression-free survival in this setting is actually not bad when you think about risk of this cohort. You can see the progression-free survival Kaplan Meier from the publications I have there, and the 12-month progression-free survival was 75% after ibrutinib, and estimated at 79% after idelalisib. They had not yet reached the median with the idelalisib cohort, which, of course, is a bit smaller. The median progression-free survival after most recent ibrutinib which is about 24.7 months, so just about 2 years. So this is really supporting that venetoclax-based therapy is effective after either BTK or PI3 kinase inhibitors. And I’ve not seen data that any other treatment is as effective as venetoclax in this setting.

I do think that with the MURANO trial the approval of the 2-year time-limited dosing scheme of venetoclax, that's attractive to offer it with rituximab despite the fact that this was studied just as continuous monotherapy, although that's a 2-year dosing scheme. And if you look, the median progression-free survival is 2 years. So you will have some patients that progress before they would get to the mark where they would stop therapy. This also supports that this population is who you want to refer for investigational therapy or cellular therapies such as allotransplant or CAR T as an investigational treatment, especially if they’re young and fit, because in CLL, 2 years is not a very good median progression-free survival.

Then the reverse, and this data is mostly looking at ibrutinib, but that should probably say BTK inhibitors after venetoclax at the top. There’s two places we’ve gotten a little bit of information on whether or not BTK inhibitors can work after venetoclax.

So, I just showed you venetoclax after BTK inhibitors. This is the opposite. The largest dataset is a multi-institution cohort study of real-world data, so this is not prospective clinical trial data. And it was in a group of 326 patients who discontinued venetoclax, looking at their experience, and 74 of them started a BTK inhibitor and that experience was also captured. And even though the numbers are pretty small, you can really see the people that had no prior BTK inhibitor, or had discontinued a BTK inhibitor when they were intolerant, can have very durable progression-free survival with a BTK inhibitor after receiving venetoclax treatment.

However, those who were resistant to a BTK inhibitor before venetoclax did not get a durable benefit. Granted, that's only 20 patients, but I think this really supports that people who are resistant to a BTK inhibitor and taking venetoclax, that's when you want to think about referral for clinical trials, cellular therapies, and those kinds of strategies.

There’s also some experience from the MURANO trial follow-up for patients that got a BTK inhibitor. They had 12 patients who got a BTK inhibitor after venetoclax where they knew what their experience was, 10 of them actually had some information as to whether or not they responded, and 100% of them did respond to the BTK inhibitor.

Interestingly, they had captured experience of 11 people who were evaluable for response and retreated with venetoclax, and only about half of them, or 55%, 6 out 11, responded.

So I do think that this is very reasonable data that BTK inhibitors should work after being treated with venetoclax. So I thought that was interesting.

DR ROGERS: So, I have a case from my clinic that I was going to share with all of you, which I think kind of highlights some of the decision-making in relapsed/refractory CLL. This patient was diagnosed in 2006. So some of these therapies I was discussing weren’t available earlier in this person’s disease course, so some of what they received is influenced by the timeframe in which they were treated.

So, this is a 79-year-old man with relapsed/refractory CLL, who was originally diagnosed in 2006 after presenting with fatigue. The original FISH panel showed deletion 11q and about, less than a year after diagnosis, he required treatment due to enlarged lymph nodes which we know is very common in patients with deletion of 11q. Tolerated FCR as an initial treatment very well, with no hospitalizations and no major side effects, other than the expected usual side effects you get from chemoimmunotherapy. What else is interesting about this person is their platelets remained right around 100,000 after treatment with FCR and had actually never recovered to above that, right around 100 level.

After FCR, of course is followed on post-therapy observation and had a reasonable remission duration from FCR, and it was between 2007 and then 2013 before he developed enlarged lymph nodes and other disease features that made treatment again necessary. As a second treatment, he actually received BR. So, finished all 6 cycles of BR and again was observed.

So the next remission duration after BR was a bit shorter, so this only about 4 years before you see the white blood cell count increase over a span of 10 months from 17 to 93 and lymph nodes increased again. So, we discussed treatment. And repeat FISH has now shown the acquisition of deletion 17p. So, of course, deletion 17p is present in only about 7% of patients at diagnosis, but increased in frequency after previous treatments. So in the chemoimmunotherapy experience, you see 20% of more of patients having deletion 17p after prior chemoimmunotherapy treatment. So it's always good to recheck that.

So treatment options were discussed at that time and in 2017 we had discussed a clinical trial and the study we discussed was the randomized Phase III between ibrutinib and acalabrutinib. So, my patient was actually very excited to participate in that Phase III trial, but unfortunately was found to have a new lung cancer actually on the screening CT study. So was unable to be in the clinical trial, but did actually get the lung cancer successfully treated. So, overall, that was good for his health. But of course, very sad he didn’t get to participate in that outstanding trial that we’re still waiting for the results of.

So he then started ibrutinib after getting his lung cancer addressed, and is doing very well on ibrutinib 3 years later, still in clinical remission. As someone receiving non-clinical trial therapy, I don’t do CT scans or bone marrow biopsies to formally assess remission because I think it's unnecessary and exposes people to extra radiation and procedures. He does have mild joint pain from the ibrutinib as well as the usual hair and nail changes. What else is interesting is his platelets went from around 100 down to like the 60- to 70,000 range and have stayed right there. So, it's not that the response isn’t good. All other markers show that he’s responded well to ibrutinib. But he did have this persistent thrombocytopenia since FCR that worsened on ibrutinib and I’ve actually seen this in quite a lot of cases. But that's working quite well for him.

At 78, I don’t think, even with a high risk feature, he’s at all interested in being referred for cellular therapy. and we have both clinical trials and obviously, venetoclax-based treatment to offer him in the future.

So the second patient is a 53-year-old woman. Both patients are actually very active. She is working full-time as a social worker. She has not too many medical comorbidities and is, overall, very well. She was also diagnosed quite a while ago, so in 2007, and was observed for 4 years after diagnosis, at which point she received FCR in 2011.

The treatment was started due to enlarged lymph nodes. She also had a good amount of blood disease at the time treatment was started. And testing before initial treatment, she was IGHV indeterminate and FISH panel negative.

She stopped FCR short of completing the 6th cycle due to prolonged neutropenia but had a nice clinical remission and was observed after treatment.

She had 4 years of benefit from FCR before requiring treatment again. And on repeat FISH panel testing, had also acquired a deletion 17p. So in 2015, we discussed treatment options with her, and at that time venetoclax wasn’t a commercial option for her necessarily — I know the initial approval was in deletion 17p — but she elected to do ibrutinib therapy. If you look at her comorbidities, these days either of those therapies would be appropriate for her. She has nothing that would limit her ability to get venetoclax, like renal impairment or heart failure, that would make the fluid and monitoring for tumor lysis syndrome problematic. And actually, she had no cardiovascular comorbidities or didn’t require blood thinner, so nothing that would make ibrutinib more problematic.

So she started treatment with ibrutinib in March of 2015 at the standard dose for CLL. All of her lymph nodes improved. She initially had some diarrhea and arthritis, but what’s more notable is about 2 months into ibrutinib treatment developed very painful skin nodules. So she actually had biopsy-proven panniculitis from the ibrutinib. I’ve seen a lot of patients with these painful subcutaneous nodules. Usually it improves with about 2 weeks of 20 mg of prednisone and in many cases does not recur. Unfortunately, every time she discontinued prednisone, she would continue to get these very painful and red nodules and, again, had the biopsy-proven panniculitis. We tried dose interruptions several times and actually tried dose reduction as well. Dose reduction is not actually very effective at decreasing a lot of ibrutinib toxicities, especially if they’re potentially on-target, because I think you’re still hitting enough of whatever is causing the side effect, either on-target or off-target with the dose reduction. But we did try that. That also was not effective. So she eventually discontinued ibrutinib.

Was observed for only several months after her brief ibrutinib exposure, but developed really debilitating fatigue so that she couldn’t really even go to her job anymore. Was struggling to go to work. Developed drenching night sweats and enlarging lymph nodes pretty quickly after discontinuing ibrutinib.

DR ROGERS: Anyway, we discussed treatment and she actually started acalabrutinib on a clinical trial for ibrutinib-intolerant patients, so people that had discontinued ibrutinib due to adverse events. So she did again actually develop panniculitis on the acalabrutinib, but it was non-painful nodules that didn’t require steroids, dose reduction, anything, and compared to the severity on ibrutinib, these were actually not bothering her. And she elected to continue on acalabrutinib. And actually, the nodules went away after a few weeks and she did very well on acalabrutinib. She said repeatedly she enjoyed taking it. Had fewer side effects and thought it was doing really well.

Unfortunately, after just over 2 years on acalabrutinib, she came to clinic with enlarging lymph nodes, drenching night sweats. Her absolute lymphocyte count had increased from 1 to about 23. And then actually, her other counts were stable, but she had clear enlargement of lymph nodes, an increase in ALC, and at that time we tested her for ibrutinib-resistance mutations and she actually was found to have a mutation in BTK. She had the C41S mutation, which is associated with resistance to both ibrutinib and acalabrutinib.

So at that time we discussed both clinical trial treatment, or a standard of care with venetoclax. And she decided to do venetoclax. Started venetoclax with a very rapid response of her CLL. So the lymph nodes went away. Her ALC actually went to less than 1. The disease response was fantastic. But she actually developed chronic diarrhea on venetoclax, which is very common with this drug, but in her case was starting to impair her lifestyle. So she was still able to work and to do what she wanted but was very worried about the diarrhea. She expressed multiple times she was very unhappy with this. We tried a lot of different supportive care things, such as loperamide. She actually noticed some dietary changes that made a difference. So she was willing to continue the drug, but the diarrhea was something that she was not happy with, with this treatment compared to the other agent she’d been exposed to.

And then that brings us to October 2020, when on the venetoclax, she has again noticed progressive disease. So she had some increase in her lymph nodes that she noticed, and her absolute lymphocyte count increased over a span of about 6 weeks from 20. It was like 5 or 6, was 20 when she came to clinic for a 3-month follow-up. Two weeks later was 50, and now we’re actually screening her for a clinal trial with a reversible BTK inhibitor, and her white count on a clinical trial screening is up to about 80. So she’s having a very rapid increase in her lymphocyte count. The lymph nodes aren’t increasing as rapidly, but she’s going to go on a clinical trial with reversible BTK inhibitor.

And then I had a discussion with her about referral for cellular therapies, because she’s in her fifties and, while I do think that people can get treatment with fewer side effects that’s highly effective in clinical trials, anyone in this age group should really speak with a physician that does transplant and CAR T about their options for that just because I do not believe there is any currently available standard therapies that are going to benefit her and she might elect to do either allogenic transplant or CAR T, which is, of course, investigational.

We’ve discussed referral for that before, but she’d always been resistant to it. But now is agreeable after having her CLL came back on venetoclax.

DR LOVE: Awesome.

So the ELEVATE-RR trial, first of all is relapse disease. But also, I don’t know, I somehow didn’t realize this, it's just del 17p and 11q?

DR ROGERS: Yes.

DR LOVE: So is it like a high risk trial?

DR ROGERS: Yes, it is. And I think there’s a couple of reasons for that. I mean one is clearly that our high-risk patients at the time that study was opened are the ones that stood the most to benefit from BTK inhibitors. The other thing is, as a practical matter, if you enroll low-risk patient, since it's an event-driven readout, we will get that after we’re both retired.

So these studies, like these agents have such a good PFS, so if you enroll low-risk CLL patients in the relapsed/refractory setting, you won’t get enough events to report your trial sooner than 2 decades from now. That's a little dramatic, but you know what I’m saying.

DR LOVE: Yeah. That's interesting though, because I guess the question is it reasonable to extrapolate the efficacy findings? Okay, tolerability fine. But efficacy findings to what everybody wants to know, which is first-line standard risk.

DR ROGERS: That is an outstanding question. I think right now, people have more or less assumed that the efficacy will be the same between the drugs based on the identical mechanism, including drug binding site, and also you don’t want to do cross-trial comparisons too vigorously, but I think you can get an idea if things are here in terms of efficacy or here in terms of efficacy. And so, people have assumed that the efficacy is the same. I don’t know that we’re going to be able to answer that for first line or not with this study.

The other thing is in the front-line setting, the CLL14, you see folks with deletion 17p have a progression-free survival that's shorter. We haven’t seen that in the front-line BTK inhibitor studies yet. It could be that they’re more effective; it could just be that they’re continuously dosed. But if you look at the front-line BTK inhibitor studies, we haven’t really seen differences between the cytogenetic risk groups yet. I expect that we will with continued follow up. But we haven’t even seen the deletion 17p does worse than 13q in the untreated setting with BTK inhibitors.

We have in relapsed/refractory CLL, but we haven’t in frontline. So we don’t even know what our high-risk patients are doing right now. We have a guess. Like I expect that our high-risk patients with deletion 17p or complex karyotype won’t do as well in the front-line setting as they don’t do as well as the other groups in the relapsed/refractory setting, but we haven’t demonstrated that. So we haven’t had sufficient follow up to demonstrate that.

DR LOVE: So, another question I had is, you were mentioning that in the idelalisib trial, there were 49% of patients dropped out because of tolerability issues. What was the main — specific tolerability issue that caused so many people to drop out?

DR ROGERS: That's a good question. I’m actually not sure I’ve seen that either. In my clinical experience, colitis is a huge one and infectious toxicities is actually a huge one with idelalisib. I’m not sure I’ve seen a breakdown from that study.

DR LOVE: It seems hard to believe that half the patients thought — that seems pretty high.

DR ROGERS: It seems hard to believe until you’ve given someone idelalisib. It is very difficult to take. There’s also — like there was a frontline study where there was a very high amount of hepatic toxicity, too. I’ve had some people take it that were on it for 3 or more years, but my clinical experience with it, too, is that it's not highly tolerable.

DR LOVE: I’ve had the impression that it's, in the short-term quality-of-life type side effects, well tolerated. And that some patients get these delayed — not immediate colitis, but delayed. So I had the impression that if you look at people in the first 6 months, they generally feel good and are doing well. But that's not your experience, huh?

DR ROGERS: Well, that might be true, but if you look at people taking BTK inhibitors, they’re tolerable for years and actually side effects tend to decrease the longer they’ve been on it. So this is kind of the opposite of that. And the hepatic toxicity seen with idelalisib is early.

DR LOVE: So, another question is, what about the issue of the patient who stops either venetoclax or BTK, for example, stops venetoclax, because that was prescribed in the trial, stops BTK because of tolerability problems. Do we know anything about whether or not patients will respond to rechallenge later in patients like that?

DR ROGERS: I think that's an outstanding question. In terms of BTK inhibitors, some of the best — or one place I can think of that kind of answers that is, there’s a dedicated Phase II study of acalabrutinib and ibrutinib intolerance. Remember, the drugs have an identical mechanism. These are people that had to stop ibrutinib for toxicities and then had to wait until their disease progressed and met criteria for progression. So you do have an interval where people have treatment. And the overall response rate to acalabrutinib in that setting was very reasonable. I think if you look at PR or PRL it was right around, I think 76%. And that does seem low for a BTK inhibitor, but if you look at the patients they’re enrolling, I think is quite reasonable. And actually, the progression-free survival is very reasonable.

So we do know that acalabrutinib works in ibrutinib-intolerant patients, so people that stopped it for a toxicity and were off treatment for a while. And I would expect that too, I’ve seen that in my clinical practice. If someone stops one for intolerance, you can do the other. It’s mostly people that discontinue ibrutinib for intolerance. People that stop ibrutinib very early, if you take ibrutinib for 6 weeks are not expected to have a durable remission after that. So I have switched some people over right away because you’re not getting disease control for any degree of time.

The venetoclax question I think is also interesting. We have that data from the MURANO trial about rechallenge with venetoclax showing 55% responded. But, again, that's a pretty adverse cohort, high incidence of deletion 17p and some of those patients had completed the study or stopped for toxicity, but I think a few of them are— actually, one of them at least had progressive disease on venetoclax and was rechallenged. So I think that as we get more experienced with venetoclax as a first targeted agent, so for people that took chemoimmunotherapy in the past, then took venetoclax or have taken obinutuzumab and venetoclax in the frontline setting, we’re going to have to figure out what rechallenge with venetoclax is like. But I think since it's not been in routine use for as long, it's going to take longer to actually get that data.

DR LOVE: So, I’ve been interviewing a lot of general medical oncologists to do case presentations. We work with you also in that regard. I’ve been amazed how many of them are doing — are sending assays for BTK resistance. Do you think that’s a reasonable thing to do in a non-trial community setting? And which assay would you do?

DR ROGERS: So, that's a good question. We actually have an inhouse assay. We have 2. We have a bold digital droplet PCR, which has very good sensitivity. So only detects BTK C41S, but can get to an allelic frequency of less than 1% and will still — it's validated to detect these mutations. We also have an Ion Torrent NGS panel that covers the entire coding region of both BTK and PCLgamma2. So there are commercially — and also, in the blood, the pathologist that developed these, can actually use flow sorting to select B-cells to do the test. So you can actually pick out mutations in patients where flow doesn’t even pick up a CLL population.

So we have a very good assay here. There are some that are commercially available, but I think anyone that's going to use those needs to look carefully as to how the assay was done, what the sensitivity is when they’re considering how to interpret the results. So I’ve been using the inhouse one and I am actually not sure which of the commercially available ones are necessarily better, because I know there’s some new ones, too. And they’ve probably improved quite a bit since a few years ago when these were coming out.

We use them here for a variety of reasons, but I do think it is reasonable in clinical practice to do that in a couple of settings. We monitor, especially our higher-risk patients on BTK inhibitors, for BTK mutations, resistance mutations, but we also can accrue people into clinical trials that had mutations, have studied molecular resistance, and have a lot to offer those patients. And just so everyone knows, the median time to developing clinical progressive disease from detection of a mutation is somewhere between 9 and 12 months. So, you have some lead time generally before you actually get progressive disease.

So, as a research question, that's a really interesting window to see what you can do so that people don’t relapse or reduce small clones. Those aren’t things that I think people are going to do in clinical practice.

The place where I think it is actually really helpful is cases where you’re not sure if someone’s progressing on it or not, like you might have seen an increase in lymphocyte count but it's during an infection, so you’re not sure. Or, you have lymph nodes that are enlarged maybe for some other reason, or if you’re not sure if it's progression.

So I think that that's actually a helpful place to use it in clinical practice. Someone that is very invested in this population, that wants to do it in a very high-risk relapsed/refractory, multiple chemoimmunotherapy treated, deletion 17p or complex karyotype patient, you could do it because it might help you decide if they have a mutation that it's time to be referred for a clinical trial if you don’t have available trials for people. So in a very high-risk population if you’re very invested in monitoring them for this, with a mind for either referral or that you have something available to offer them. I don’t think that it is a standard to switch therapy because of these mutations. Right now that's a research question.

Those are kind of the settings where I’d say it could be used. And I would just make sure that whoever is using it looks carefully of what the assay is.

Novel Strategies Under Investigation for Patients with CLL — Tanya Siddiqi, MD

DR SIDDIQI: So I’m here to talk about the novel strategies under investigation for patients with CLL/SLL, and these are some of the things that we’ll go over today, talking about BTK inhibitors and BCL2 inhibitor combinations, coming back to CAR T cells in CLL, with some data going over the TRANSCEND CLL 004 study, and then some ongoing and interesting targets, newer strategies coming briefly, and then a couple of patient cases to discuss.

So I’ll start with front-line ibrutinib plus venetoclax clinical trials. There are a couple of prominent trials to discuss, CAPTIVATE Phase II trial first, and then the UK CLARITY Phase II trial next. And I’ll show some representative data from these studies.

So the CAPTIVATE trial is basically a Phase II study that is for patients with previously untreated CLL/SLL who have active disease and need treatment. Age should be less than 70 years, and ECOG Performance Status 0 to 1. And the treatment plan of this trial was to give 3 months of ibrutinib full-dose lead-in phase, and then at cycle 4 onwards to introduce and ramp up the venetoclax, and then continue the 2 together for a total of 12 cycles beyond the 3 cycles of the ibrutinib lead-in phase.

So at cycle 16, once restaging was done, we checked minimal residual disease testing in all patients, and if they were confirmed undetectable MRD at that timepoint, by flow cytometry down to a level of 10-4 or lower, patients were randomized between ibrutinib maintenance versus placebo. But this was a double-blinded randomization. If patients remained MRD positive or you could not confirm undetectable MRD on serial testing at that timepoint, patients were randomized between ibrutinib single-agent maintenance versus continuing both the ibrutinib and the venetoclax together as before. And this was an open-label randomization. People know what they’re taking at that timepoint. And 164 patients were enrolled onto the pre-randomization portion of this study in this MRD cohort. There is another cohort of fixed-duration therapy, where everybody stops after the 12 cycles of combination ibrutinib plus venetoclax. And of course everybody did get the initial 3 months of ibrutinib single-agent therapy. So there were 159 patients on that fixed-duration cohort, and I’m not going to talk about that yet because we’re going to see the first data of that emerge at ASH this year. But I will talk about the MRD cohort update that we’ve seen so far, and this will be updated further in ASH this year.

So you can see that at the completion of 15 or 16 cycles, on the initial portion of the pre-randomization portion of this study there were high rates of undetectable minimal residual disease achieved in peripheral blood and bone marrow of these patients, 75% in peripheral blood and 72% in bone marrow had achieved a best response of undetectable minimal residual disease. And there seems to be a high concordance between blood and bone marrow as far as flow cytometry was concerned, for MRD testing, 91%. In the 164 patients who were all treated, these are the numbers that show the high MRD, and it appears, that the MRD undetectability actually improves over time over the cycles, so we started testing at 7 and 10 cycles and subsequently. And by the time patients reach 15 cycles the undetectable MRD rates were much higher compared to at cycle 7 and cycle 10.

And then at 15 months, or after 15 cycles, 98% of patients in this pre-randomization portion of the study remained progression free, and there were no deaths from the treatment on this study until that timepoint. And of course the postrandomization updates will be given at ASH this year.

One interesting thing to mention, the reason why the ibrutinib lead-in was given was in order to try to do some debulking and to limit the tumor lysis risks of venetoclax before it was introduced. And so what we did see on the study was that there was reduction in the lymph node burden of patients at the end of the 3 cycles of ibrutinib. And as expected with single-agent ibrutinib, initially there was lymphocytosis, a redistribution lymphocytosis that can occur. But by the time 3 cycles were done of the lead-in single-agent ibrutinib portion of the study before venetoclax was introduced, lymphocytes had started coming down nicely as well.

The other trial to talk about is the UK Phase II CLARITY study, and that involved about 53 or 54 previously untreated CLL patients requiring therapy. And this is just a representative slide, again to show the MRD responses of those patients over time. So these patients also continued ibrutinib and venetoclax for up to 2 years of treatment, and you can see these purple bars that are going up on the right side of the peripheral blood, as well as the bone marrow bar graphs, the purple bars indicate undetectable MRD, essentially, down to a level of 10-4 or lower. And you can see that that number is rising the longer patients are staying on the combination treatment. And this study is being followed up by a Phase III trial that I’ll mention in a minute as well.

In the relapsed/refractory setting there are a couple of trials that are prominent to me that are evaluating ibrutinib plus venetoclax combinations. And the first trial is MD Anderson’s investigator-initiated Phase II trial that Dr Jain published last year. It’s a front-line trial for patients with high-risk CLL, and older patients with CLL, receiving ibrutinib plus venetoclax for up to 24 cycles, or a couple years again as well. And again there was a lead in of ibrutinib for the first 3 months, followed by introduction and ramp up of venetoclax, and then both drugs were stopped after 24 cycles of combination.

And you can see again that undetectable MRD, which is the orange bar graph below, is increasing in number over time. So there were about 80 patients who started the trial, 75 I think were evaluable after completing 3 cycles of ibrutinib monotherapy. And then subsequently up to 26 patients at the time of this publication had completed 18 cycles of the combination therapy and thereafter. We’ll see what the latest updates are on these patients as to were they able to stop therapy after 24 cycles, and then what happens to them when they stop therapy? How long does their remission last? I think we need to see that over time.

So very exciting because in the front line, as well as in the relapse setting, we’re starting to see that there are much, much higher undetectable minimal residual disease responses being seen with the combination of ibrutinib plus venetoclax without even a CD20 monoclonal in the picture. And we do not see this with just 1 of the novel inhibitors by themselves, certainly. And also my sense is that we do not see this with one of the novel inhibitors plus a CD20 monoclonal antibody like we’re seeing here with the 2 novel agents together.

So exciting data we have at City of Hope and Stanford, another Phase II ibrutinib plus venetoclax combination trial for relapsed/refractory CLL, which has completed accrual. It’s a small study, about 20 patients. We’ve completed accrual, and we’re following them over time. I’ve just started having a couple patients who finished the 2-year period and are going to be now followed over time to see how they do and whether or not their disease stays in remission longer because they’re all in very good undetectable MRD remissions.

Coming down to the ongoing Phase III trials, so combining these novel agents together in the Phase III setting is now being studied in the US, as well as in the UK, and the ALLIANCE trial and ECOG-ACRIN trials have very similar studies for patients either above the age of 70 or below the age of 70 respectively, and the combination being tested is a randomization between ibrutinib plus obinutuzumab, which is a CD20 monoclonal antibody, versus ibrutinib plus venetoclax plus obinutuzumab.

So in this situation they’re trying 2 drugs versus 3 drugs to see if you can get a deeper remission and may be able to have more time-limited therapy with the IVO combination compared to the IO combination, and whether or not people above the age of 70 can tolerate that versus younger patients. We will see the results of this over time as we get the results. I can tell you that the ECOG trial is accruing very well at our center. The ALLIANCE trial is a little bit slower because patients above the age of 70 may have a tougher time getting through the triple-drug therapy and may be a little bit more hesitant to participate in this particular trial. But we’ll see the data when we analyze it down the line.

And in the UK the FLAIR trial is a Phase III trial which is comparing ibrutinib alone in a Phase III setting, ibrutinib alone versus ibrutinib plus rituximab, which I believe is an arm which has already completed accrual and is not accruing anymore, versus FCR against ibrutinib plus venetoclax for 6 years, I believe, is the plan. But we’ll wait to hear more from our UK colleagues about the FLAIR trial as it evolves and as we get new data around it.

The next thing to discuss on the agenda is CAR T-cell therapy in CLL. And currently the trial that is one of the larger multicenter CAR T-cell trials in CLL is the TRANSCEND CLL 004 study, which is evaluating lisocabtagene maraleucel, or liso-cel for short, in patients with relapsed/refractory CLL. And all patients, after screening, they get enrolled and they undergo leukapheresis. And while their T cells are being manufactured over a period of 3 to 4 weeks, bridging therapy is allowed if needed to maintain their disease. Restaging needs to be done before starting lymphodepletion for 3 days with fludarabine and cyclophosphamide, followed a couple days later by liso-cel infusion, and then follow up on the study.

The key eligibility criteria, shown at the bottom left here, so everybody needs to have relapsed/refractory CLL, and they all needed to have failed a BTK inhibitor. They could also be ineligible for a BTK inhibitor because of medical conditions, but in reality in the Phase I portion that I’m going to talk about here, 23 patients that we will update the data on at ASH this year as well, all were exposed to ibrutinib therapy in the past. And aside from having had a BTK inhibitor as part of the eligibility, patients with high-risk CLL needed to have failed a total of 2 or more prior lines of therapy.

Patients with standard-risk disease needed to have failed a total of 3 or more prior lines of therapy. ECOG Performance Status 0 to 1 was allowed on the study. Dose-escalation design was the mTPI-2 design, and a 28-day DLT period was observed in this Phase I portion of the study. And the primary objectives you can see on the right there, safety and to determine the recommended cell dose for the Phase II expansion of the study. And there were some exploratory objectives as well. Two (2) dose levels were evaluated, a total of 23 patients were on this Phase I portion of the study. And you can see that their baseline characteristics are shown here. Median age was 66. About half were male.

And further down you can see that a majority of patients had advanced-stage disease and high-risk features of their disease, and at the bottom you can see that all patients had received prior ibrutinib.

A majority of them had actually progressed on ibrutinib. There were a couple of patients who were intolerant to ibrutinib but were still eligible for this study. And then interestingly there were 9 patients at the time I presented this data at ASH last year, and this will be updated at ASH this year, but 9 patients who progressed not only on ibrutinib but had also failed venetoclax at the time that they enrolled onto this trial.

And you can see that for this double-refractory population, if you will, on the right, the baseline characteristics were fairly similar to the entire group of patients. And these were the CAR T-cell-related side effects that we followed among these patients. In all patients there were very few Grade 3 cytokine release syndrome events. Only 2 patients had Grade 2 cytokine release syndrome. No patients had Grade 4 CRS. As far as neurological toxicity is concerned, there were 5 patients who had Grade 3 or Grade 4 neurotoxicity, but all these events were resolved.

And further down you can see the usage of tocilizumab and steroids on this study. And there were no Grade 5 events of CRS or neurotoxicity in this Phase I portion of the TRANSCEND CLL 004 trial. And in the double-refractory subgroup of patients you can see that the side effect profile was fairly similar to the whole group of patients.

And as far as responses are concerned, there was a very good overall response of 81% in the evaluable 22 patients, with 45% CRs. And in the double-refractory subgroup of 9 patients who had failed both ibrutinib and venetoclax in the past, there was a very good, 67%, CR rate and 89% overall response rate. On the right side you can see that the undetectable MRD rates were also very good among these patients. Twenty (20) patients were evaluable for MRD, and 75% undetectable MRD by flow cytometry in the peripheral blood, and 65% in the bone marrow by next-generation sequencing. And even better in the double-refractory group of patients, 87% and 75% respectively. The median follow up was short at the time we presented this study last year, 11 months, but we will update the follow up at 24 months for ASH this year.

This swimmers’ plot basically shows how these patients have done over time. So at the bottom panel is for the subgroups who failed both ibrutinib and venetoclax, whereas the rest of the patients on the top panel above, 68% of patients had a response by day 30, which is the very first vertical column you see, which is the first response-assessment timepoint for these CAR T-cell-treated patients. And 27% of patients evolved their response, or improved upon their response, over time, like from PR to CR et cetera. 83% of patients with a PR or CR at 6 months remained in response by 9 months, and 8 patients at the time of this data were in response at 12 months or longer. At 24 months now we’ll update the data at ASH this year, and we’ll see how far the longer-surviving patients without disease go, or without progression go.

But 80% of patients who achieved an undetectable MRD in their blood seemed to have maintained their response, meaning they don’t lose their MRD undetectability or relapse with CLL. There were a few patients, maybe 3 or 4 patients, who relapsed with Richter’s transformation, interestingly, even though there was no sign of CLL in at least 3 of those 4 patients. And there was maybe 1 or 2 patients who actually progressed with CLL.

So very encouraging early data from this CAR T-cell trial. There are other targets and other trials with the same target as CD19 ongoing currently, the ZUMA-8 trial is studying axi-cel

At the Fred Hutchinson Cancer Center the JCAR014, which is the precursor to liso-cel if you will, is being studied in combination with ibrutinib. At UPENN the CTL019, which is a precursor to tisagenlecleucel, if you will, is being combined with ibrutinib and studied in CLL. And then there are novel targets that are being evaluated, like ROR1 and CD22 in CLL. There are also off-the-shelf allogeneic CAR T-cell trials that are ongoing that take CLL patients.

And it remains to be seen whether there are any significant GVHD-type (graft versus host disease-type) side effects. I haven’t heard of any, which is great. And then I’m not sure how many CLL patients have been treated on the off-the-shelf trials yet. But it certainly is exciting to think about that in terms of the ease with which you can treat patients rather than having to first leukapherese, and then manufacture, and then ship back, and the waiting time and all that stuff that we deal with currently with CAR T cells, or autologous CAR T cells.

So certainly more interesting and exciting things coming in the future as far as CAR T-cell therapy is concerned. There are also bispecific antibodies that are being developed in CLL. So there’s a lot of things to discuss, but the goal I feel of CAR T cells is, as a living drug, is to try to get patients to a cure in a disease which is generally considered to be an incurable disease. And so hopefully, hopefully we can get there, maybe with combinations, maybe with different targets or combinations of targets.

And then in the end I’ll round up with a couple of patient examples, my own patients who I’ve treated over time. I have many such examples, but 1 patient was a 67-year-old gentleman when I saw him. He was seen in September of 2017 for CLL that had some poor-risk features of unmutated IGHV and ZAP70 at the time when he was diagnosed in 2006. He was treated at UCSD for the longest time by Dr Kipps, et cetera, and so he was on different trials. And so he received rituximab/lenalidomide initially for a while, but then progressed, and he received high-dose methylprednisolone and ofatumumab for a few cycles, had a partial remission then progressed again.

And then he was placed on ibrutinib initially in combination with rituximab, for a few years, actually, until 2015, but then he developed this blistering rash all over his body, and was attributed to ibrutinib, so he stopped that drug. In 2016 he was started on venetoclax and initially had a partial response, but then a year or a year and a half later he progressed and received high-dose methylprednisolone, again, with obinutuzumab in combination, at which time he came to me to be evaluated for our liso-cel TRANSCEND CLL 004 study. He was eligible. He enrolled onto the trial.

And while we did leukapheresis and while his cells were being manufactured, he had very bulky and rapidly growing, very painful lymphadenopathy, without transformation. And so we controlled his disease with idelalisib, which is one of the agents he had not had yet. And it partially kept him together until his liso-cell cells were available in early 2018. We gave him 3 days of fludarabine and cyclophosphamide in the hospital, followed a couple days later by the liso-cel cells, on January 31, 2018.

He had all the complications you can imagine, probably because of the bulk of his disease: tumor lysis syndrome, cytokine release syndrome, neurotoxicity. And then subsequently when he recovered from all that he also had CMV reactivation.

Anyway, at day 30 he was in MRD-positive remission that then deepened to an undetectable MRD by I think it was about 3 to 6 months timepoint. And since then he has remained in undetectable MRD. We call him undetectable MRD but partial remission because he never had a normal-sized spleen subsequently, and he always had a little lymph node here or there which was above normal in size.

So he remains in remission with undetectable MRD in the marrow and peripheral blood almost 3 years later and doing well. He’s living a normal life, essentially. He’s needed IVIg periodically for hypogammaglobulinemia, which is a known long-term side effect of CAR T cells. And he’s had 1 or 2 infections along the way like pneumonia, et cetera, but by and large he’s been able to get his knee replacement surgeries and just live a normal life as much as possible without progression of his CLL or relapse of his CLL again. So that’s a very nice example of what CAR T cells can do, because if they work, they work extremely well.

And the second patient is a 40-year-old man now, but when I saw him he was 36 years old, previously untreated CLL, good-risk features of deletion 13q. I don’t think we were ever able to get his IGHV mutation status accurately at that time. But anyway he had rapidly-dividing CLL cells, so rapid lymphocyte-doubling time, and progressing lymphadenopathy soon after his diagnosis in 2016.

And he consented to participate on the CAPTIVATE Phase II trial, which was open at that time. He enrolled onto the MRD cohort. He finished 16 cycles, achieved an undetectable MRD remission, randomized to ibrutinib versus placebo, which is a double-blind randomization on that part of the study. And he’s been on this since January of 2018, so we don’t know if he’s getting ibrutinib or placebo, but he remains in an MRD-undetectable remission, working full time, living life normally but on therapy. And so we will follow him, and we’ll see if we’ll ever find out which treatment he’s on, placebo versus maintenance, and we’ll see how long he maintains his remission.

DR LOVE: So that was awesome. If I could just follow up with a couple of questions.

So one thing I wanted to ask you about in terms of CAR T, I noticed your 1 patient had TLS. And I was wondering whether TLS is more common with CAR T in CLL than CAR T in other diseases, like for example large cell?

DR SIDDIQI: Yeah, interestingly I have not seen it a lot in large cell lymphoma. I think it may be a little bit more common in CLL, maybe because of circulating lymphocytes. I’m not sure. I think ALL may also have a similar issue, probably because of circulating lymphocytes or lymphoblasts. I’m not 100% sure, but yes, you’re right. It’s not common, even in CLL it’s not very common, but I have seen it more in CLL than I have in large cell lymphoma, personally. I’ve seen it in mantle cell as well by the way.

DR LOVE: That’s interesting.

DR LOVE: So another question I had for you is I wanted to ask you, I don’t think there’s been a Phase III trial comparing venetoclax alone to venetoclax/obinutuzumab, and if there hasn’t been how would you compare them directly? If there was a Phase III trial what do you think it would show?

DR SIDDIQI: I think it would show deeper, maybe deeper responses, earlier responses. I’m not sure it would necessarily show longer durability of responses if you talk about time-limited therapy with venetoclax and obinutuzumab. So if you stop the venetoclax, and you’ve had 6 months of obinutuzumab prior to that, like the CLL14 trial, then you get a deeper and a faster remission, but I’m not sure you’ll maintain a remission off of venetoclax. And so venetoclax single-agent therapy, you just stay on it long-term. You might have the same durability of response even though not a deeper remission.

DR LOVE: The other thing is the question of MRD with the combination, the trials that you were talking about to me it didn’t look that much higher than what you see with venetoclax/obinutuzumab.

DR SIDDIQI: I think in the front-line trial it seems to be a little bit more, the venetoclax plus ibrutinib undetectable MRDs to me looked higher in the CAPTIVATE trial. Not so much in the CLARITY trial as in the CAPTIVATE trial. You might be right.

DR LOVE: Did you think it was going to be higher?

DR SIDDIQI: I personally did think it as going to be higher. I think now they’re banking on the fact that maybe the remission might last longer. We kind of know that with venetoclax/obinutuzumab people do start relapsing within a few months, or within a year. The bottom line is I don’t think the stopping of venetoclax with the VO combination was based on MRD, right? So even if they’re MRD positive they still stopped at 12 months. So I think it’s interesting. All these combinations are certainly very expensive, whether you go with 2 pills or 1 pill and an infusion. So I’m not sure what the right answer is. I think durability of response might make a difference. But there seems to be a little bit more MRD undetectability with the 2 novel drugs, novel pills I mean.

DR LOVE: The other thing I was curious about is you’ve had experience with the combination of ibrutinib and venetoclax. Are there any issues that come up in terms of tolerability? Like they get side effects, and you don’t know which one to stop? Or is it more tricky to give in terms of managing side effects?

DR SIDDIQI: Right. You mean ibrutinib plus venetoclax, right? Not the obinutuzumab?

DR LOVE: Right. Right, yeah.

DR SIDDIQI: Yeah, so I have had that situation a few times. If it’s something as simple as bleeding, not simple, but something as obvious as bleeding, then it’s the ibrutinib. If it’s an infection, then you’re kind of stuck. You have to stop both and then rechallenge the patient later.

I’ve had situations where it’s just something like neutropenia, right? And then I feel like if they were not neutropenic with the first 3 months of ibrutinib, but the neutropenia set in once the venetoclax was introduced, then I just, personally, I taper down, take down the venetoclax a notch first and see how that goes. Usually that’s enough to help patients. So you’re right, it can be little bit tricky.

DR LOVE: Another question is could you describe a patient you think would be perfect to send to a CAR T trial in CLL. Or when do you start thinking about referral? Are you basically looking for refractory to BTK and venetoclax? Or anything more specific?

DR SIDDIQI: Yeah, right now the way that the study is enrolling patients, because it’s still enrolling, this TRANSCEND CLL study, we are looking for patients who have progressed on ibrutinib or have not been able to tolerate ibrutinib, or I should say BTK inhibitor now that we have more than 1 available, and also progressed on venetoclax. That’s the niche that they’re looking at right now because it’s hard in CLL to say go get CAR T cells when you still have venetoclax to try, right?

So right now the niche that is being evaluated is that double refractory to novel agents at this point. But I would say that instead of waiting until patients have failed 3, 4, 5, 6 lines of therapy, send them sooner, as soon as they meet eligibility so they’re in better shape. They can get through the month of intensive follow up and treatment.

DR LOVE: And in terms of that, what are your thoughts in terms of age and performance status for CAR T as opposed to, let’s say as a benchmark, autologous transplant in general. Do they need to be in as good a shape or maybe not quite as good?

DR SIDDIQI: No. I think they can be in a little bit poorer shape, to be honest. I think transplant is tougher, even autotransplants are a little bit tougher. We have stricter criteria about meeting PFT and echo and EKG and whatnot standards, whereas the oldest patient I’ve taken to CAR T cells is 83 years. I wouldn’t have done an auto on that particular patient. For instance, there’s more and more examples of people in their 80s getting CAR T cells, or higher 70s. So definitely there’s more room.