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May 15, 2019

ASCO Daily News Editor-in-Chief, Dr. John Sweetenham on Hematologic Poster Presentations To See at #ASCO19


Welcome to the ASCO Daily News podcast. I'm Lauren Davis. And joining me today is Dr. John Sweetenham, the ASCO Daily News editor-in-chief. As attendees are getting ready for the annual meeting, Dr. Sweetenham will highlight some of the poster sessions and hematologic malignancies that will capture the attention of attendees. Dr. Sweetenham, welcome to the podcast.

Thank you. It's good to have the opportunity to talk.

We're glad you're here. For attendees who are interested in hematologic malignancies, what areas in this specialty are you most looking forward to?

So I think at ASCO this year in heme malignancies, I would characterize a lot of the studies that are being presented in poster format as confirmatory, or long-term confirmation of some earlier results. But I think they're no less interesting because of that. And I think that there is some important follow-up data, particularly in CLL, and some important confirmatory data for CAR T-cell therapy and hematologic malignancies.

Added to which, I think there are a lot of potentially exciting new agents for the treatment of acute myeloid leukemia, in particular. That's been an area of a lot of interest and a lot of new treatment developments over the last two to three years. And I think that the poster sessions at ASCO this year confirm that trend is still ongoing and that the outlook for this very challenging group of patients is improving.

That's great. What else can attendees expect this year? Any surprising or practice-changing data?

I think, in terms of practice-changing data, I would list some of the specific abstracts which I think, as I mentioned earlier, are really confirming the importance of some agents and certainly will confirm practice changes that have happened over the last couple of years. To give you a couple of examples of that, perhaps I'll start with chronic lymphocytic leukemia. The RESONATE study was a very important study for patients with relapsed and refractory CLL, which assessed the use of ibrutinib, a once-daily Bruton's tyrosine kinase inhibitor against ofatumumab in this group of patients.

The original study was published in The New England Journal, but at the meeting this year, there is mature follow up, a now six-year follow up of patients treated on this study. And the encouraging news is that the initial ibrutinib treatment, which was originally shown to produce improved overall survival, that has been confirmed. So the median duration of ibrutinib treatment on this study is now 41 months. So it really is quite extensive follow up at this point.

And encouragingly, the overall survival and median progression-free survival benefits, which was 44.1 months for the ibrutinib arm versus 8.0 months for the ofatumumab arm, that has been maintained. And so it's clear that the long-term therapy with ibrutinib remains highly effective and that the number of patients who are required to discontinue ibrutinib because of adverse events is fortunately relatively low.

So I think it confirms ibrutinib now across just about the entire spectrum for CLL as the important treatment, both in front line for those patients who are previously untreated, and in second and subsequent-line therapy for those who've had some other agents as the first-line treatment. I think that is very important.

And along with that, there is a cautionary note from a study which explored the second cancer incidence in CLL patients receiving BTK inhibitors. Contextually, there's been quite a lot of data, over the years, exploring second malignancies in patients with CLL. In this particular study, they did actually suggest that there probably is a somewhat higher incidence of second primary neoplasms in patients who are taking ibrutinib for CLL.

And those included cancers at the lung, melanoma, prostate, and bladder cancer. So I think, at this point, this is just an alert and something that we will need to watch closely as it does appear as if there is a slightly elevated risk of second cancers in these patients.
And then one other follow-up study, which I think is of importance, is the fact that second-generation BTK inhibitors are now really starting to gain some traction in CLL. And there was a nice study presented in poster format which is going to explore the use of acalabrutinib, which is a second-generation BTK inhibitor, in patients who were intolerant of ibrutinib.

So for those patients who need to discontinue ibrutinib because of adverse events, the second-generation acalabrutinib is effective with an overall response rate of 77% and well-tolerated so that if patients are in tolerance of ibrutinib, they certainly do have other options.

I think, also, to complete the CLL field, there is a great deal of interest in the potential use of CAR T-cell therapies for CLL. And although it is very immature and the data to be presented at ASCO poster are very limited, it is just worth pointing out that there is an ongoing ZUMA-8 study for patients with relapsed and refractory CLL exploring the use of CAR T-cells. And I think that's going to be important. It will be very interesting to watch how that develops over the coming year or two.

Another area which I think is very important is that we're starting to see now that there are some studies which are really exploring not only the disease-related benefits of some of these therapies, but are also starting to look at patient-reported outcomes. And there are two posters, in particular, which I think are interesting in this regard. There is one study which looked at patient-reported outcomes in patients with Waldenstrom's macroglobulinemia who were treated with ibrutinib as a single agent or in combination with rituximab.

So in the iNNOVATE study, it was demonstrated that ibrutinib plus rituximab produced higher sustained hemoglobin improvements and meaningful improvements in other laboratory parameters when compared with placebo and rituximab. In this study, the investigators have gone a step further and have actually looked at patient-reported outcomes and shown that, in addition to the standard response improvements that are seen, there's a clear improvement in patient-reported outcomes associated with the use of this novel combination with ibrutinib and rituximab.

And so along with the improvements in anemia, for example, there are marked improvements in fatigue-related symptoms, constitutional symptoms. And the clinical improvements are truly meaningful. And that's actually mirrored in a different context, but in patients with multiple myeloma who were previously undiagnosed and treated with a novel combination of daratumumab, lenalidomide, and dexamethasone versus the same regimen but without the daratumumab.

And here, again, there is important patient-reported outcomes demonstrating that, essentially, with the novel combination, patients feel better more quickly. So the clinical responses that have been demonstrated on that trial are confirmed by patient-reported outcomes, which demonstrate that patients are truly feeling better. So, again, I think at the patient level, these are very important data.

Some other things that I think are important to look out for at this year's meeting, there are a series of posters which explore novel therapies for acute myeloid leukemia and myelodysplastic syndrome. Without listing these in great detail because there are several of them, I would simply say that these studies add to the extraordinary expansion of available treatment options for patients with AML that we've seen developing over the last few years.
And I think that the treatment landscape for these patients is really changing now. Sequencing prior to therapy is becoming important as more novel targets are identified, but consistent with the trend we've seen in the last two or three years, more important emerging therapies for patients with acute myeloid leukemia.

Shifting gears for just one moment and looking at patients with B-cell lymphoma, and specifically aggressive non-Hodgkin lymphomas, I think that there are a couple of studies here which show promise, although certainly I wouldn't categorize them right now as being practice changing, but the findings are interesting. One of those is, again, in the context of CAR T-cell therapy.

So it's difficult to talk about heme malignancies at the moment and not talk about CAR T-cells because there's such a lot of buzz and excitement around those. And one of the areas where this intervention is now FDA approved is in the treatment of patients with relapsed, aggressive non-Hodgkin lymphoma, particularly diffuse large B-cell lymphoma. And that was the subject of the so-called ZUMA-1 study, which was a phase 1/2 study of axicabtagene ciloleucel in patients with refractory large B-cell lymphoma.
The study reported out some months ago now, but one of the concerns that some of us have had is that this may be a very reasonable treatment for the young patients with a good performance status who typically don't represent the bulk of patients with large B-cell lymphoma. But what about those patients who are older? And how do they tolerate this therapy? And what's the outcome?

And in a study that's going to be reported at ASCO this year, the investigators of the ZUMA-1 study conducted a specific subset analysis on that group of patients who were aged 65 years or older. It's a small group. But I think the take-home message from the study is that the outcomes in this group, in terms of the overall response, complete response, and overall survival rates are very comparable to the younger age group. And the toxicities are very comparable to the younger age group, as well.

So I think this is important that age, in itself, may not be a barrier to the applicability of CAR T-cell therapy. And that's a very important message. The flip side of that is that these one, it seems a pretty highly selected group of patients aged 65 years or older. And certainly, that's reflected in the performance status and the IPI scores of these patients as reported in the abstract.

So they may be a highly selected group of patients aged 65 or over with this disease, but nevertheless, I think they're quite compelling results. And I think it speaks to the broader applicability of this therapy in patients with relapsed, aggressive lymphoma. The big remaining question being, how are patients and perhaps, more importantly, how is the health system, as a whole, going to cope with the cost and the financial toxicity associated with this very important new treatment?

Again, on the subject of aggressive B-cell lymphoma, there is one more study which caught my eye. And it's interesting for a couple of reasons. This is a study which explores the use of a PD-L1 inhibitor, durvalumab, alongside either the R-CHOP regimen or the R2-CHOP regimen in patients with newly diagnosed high-risk diffuse large B-cell lymphoma. And this includes patients with double-hit lymphoma where we know the prognosis is particularly bad.
These are very preliminary data in which a standard therapy with R-CHOP or R2-CHOP is being modified by the addition of this anti-PD-L1 monoclonal antibody. At the moment, the data are very largely related to adverse events. And there are some very preliminary outcome data, but probably difficult to read anything very much into those.

The interest, to my mind, is that some recently-published data have suggested that checkpoint inhibitors in aggressive B-cell lymphoma may not be a particularly effective treatment modality. But I think it will be very interesting to see whether the combination of checkpoint inhibitors plus regular chemotherapy have the opportunity to improve outcome.

So I think this is a study in progress. It's way too early to draw any conclusions at the moment. But I do think it's important not to write-off the role of checkpoint inhibitors in aggressive lymphomas without conducting important studies like this one which look at combination therapies rather than just the single-agent therapy.
And then, in conclusion, one other study which I think is quite important, again, presented in poster form, and this was a study that looked at survival disparities of diffuse large B-cell lymphoma in a community-based cancer center. And essentially, this was a retrospective study which looked at 381 patients who had aggressive lymphomas and looked at outcome according to race and showed very highly significant disparity in survival for those patients who were African American where their overall survival was markedly inferior to other patients with a hazard ratio of 2.19.
So it was a really very marked difference in outcome. The explanation for this is not entirely clear from the abstracts. But I think it's something which is very important for us to take note of.
So that is just a quick run-through some of the poster presentations that caught my eye at the meeting this year. I think that there will be some important practice-changing studies presented during the oral presentations. And I would certainly strongly encourage folks to be at those. But I think that, as always, there are some important highlights in the poster presentations. And I could go on with many more, but I think that those probably be the highlights from my perspective.

Sounds like some promising studies to look forward to. Again, today my guest has been Dr. John Sweetenham. Thank you for being on our podcast today.

Thank you. Great to have the opportunity to talk.
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