Dr John Leonard (Host): Welcome to Weill Cornell Medicine CancerCast, conversations about new developments in medicine, cancer care, and research. I'm your host, Dr. John Leonard. And today is my annual Leonard List episode, where I will be talking about the 15 most interesting lymphoma, as well as a few blood cancer-related, abstracts to be presented at the 2024 American Society of Hematology Annual Meeting.

So, what is the American Society of Hematology or ASH? That is one of the largest, if not the largest, professional organization around blood cancers and non-malignant or non-cancerous blood disorders. It is a place where experts in this area and others interested in the field or studying in the field or doing research gather each year, typically in December. This year, it will be in San Diego. This is where tens of thousands of people get together.

There are lots of different topics and educational sessions and other programs as well as a lot of gatherings where people learn and work and collaborate. There are several thousand what we call abstracts or summaries of research work that are submitted in advance of the meeting. And in the few months leading up to the meeting, they are reviewed by subgroups of experts on the individual topics of focus, which they are related to. And then, the most outstanding or impactful abstracts are presented at the Plenary Session. It's small in the number of abstracts, generally around six abstracts are presented. And really, the whole meeting comes to a halt to hear these high-impact abstracts. And then, there are oral sessions, probably hundreds of oral sessions, focused on different topics. And there are poster sessions where, as the name implies, the authors put up a poster with their work and people browse around and look at the abstracts and can talk and discuss and ask questions. And then, certain abstracts are also submitted online and reviewed online only.

Over seven years now, I have been collecting a group of abstracts that I think are impactful, interesting, thought-provoking or really important for patients and physicians and researchers to know about. Maybe some off-the-beaten path sorts of abstracts that I feel like highlighting. And in the 10 days leading up to ASH on Twitter, I have counted down with one abstract per day and given you a few thoughts on those for those who follow along. And then, when we started the CancerCast podcast, I decided to, in advance of the meeting, reveal the ten abstracts that I was going to count down as well as five bonus abstracts and perhaps give a little bit extra information around those, given that you're limited in what you can talk about on Twitter.

And so, that's what we're here to do today. And I've gone through the list and picked out some abstracts. I am sure that some of you who look at these or listen to this might think that I've left out some things, or maybe some of the things I've chosen are not the top of your list, and that's fine. These are just to be thought-provoking and to call attention to some areas that I think are either important, interesting or warrant a little bit of discussion. And there's also an intent to be a little bit provocative or not so run-of-the-mill sometimes as I look at these. Why don't we get into it, and we'll start the countdown.

So, Abstract Number 10, the first of my choices, but number 10, as we count down from 10 to 1, and then go to the bonus ones, is Abstract 3030, entitled “Treatment and Outcomes of Stage I-II Pulmonary MALT Lymphoma: A Multi-Institutional Observational Study in Japan”. MALT, or mucosa-associated lymphoid tissue, is a type of indolent lymphoma that tends to occur in mucosal surfaces, including the gastrointestinal tract, the skin, other areas where there are mucosal surfaces of the body, and one of those areas is in the lung. And in that case, it's called pulmonary MALT lymphoma. These are often found when a patient has some symptoms, maybe a cough or shortness of breath leading to a chest x-ray. Sometimes they're an incidental finding where somebody who's been a smoker or had other lung issues gets a chest x-ray. One is worried that there's a cancer of some type, and it turns out to be a MALT lymphoma rather than perhaps a lung cancer.

About 7% of the MALT lymphomas occur in the lungs and there are lots of different approaches and little in the way of randomized studies to say which approach is better. And so, this is a large series from 31 institutes in Japan, patients identified over about 10 years or so. And the investigators found about 200 patients with pulmonary MALT lymphoma, about two-thirds of them had stage I or II disease, meaning relatively limited in its size and distribution.

So, the bottom line was that this group had a median age of 68, and mostly stage I disease, mostly localized disease, and generally good risk patterns. They were treated at the discretion of the treating doctor in a number of different ways. Watch-and-wait in just about half of patients, surgery in about a third of patients, and then small numbers received rituximab, the anti-CD20 antibody monotherapy, or chemoimmunotherapy.

I think the take-home from this, again, remembering that half the patients had no treatment, at least initially, was that the four-year overall survival was about 95%, and basically 80-85%-90% of people really didn't need intervention over the course of roughly four years or so. I've tended to treat these patients conservatively and often just observe them over years. You sometimes have to tease out, is this lesion causing any symptoms? But this, I think, is reassuring that no matter how you decide to approach these patients and even if they are observed, the outcomes can be quite good and these patients can go at least several years not needing any therapy, which is certainly encouraging and reassuring.

Next, we're going to move to my ninth selection in the countdown. This one is a 9A and 9B. Occasionally, I pick two abstracts that are similar in theme and give them an A and B.

And so, 9A is Abstract 862, “Efficacy and Safety of Odronextamab in Relapsed and Refractory Marginal Zone Lymphoma: Data from the Relapsed/Refractory MZL Cohort in the ELM-2 Study”. Dr. Kim is the first author. And 9B is Abstract 3032, “Limited Duration Loncastuximab Tesirine Induces a High Rate of Complete Responses in Patients with Relapsed/Refractory Marginal Zone Lymphoma - Report of a First Interim Analysis of a Multi-Center Phase II Study”.

So, why did I pick these? I'm continuing with the marginal zone lymphoma theme. Marginal zone lymphoma can also have advanced stage disease, where it involves lymph nodes as well as areas outside of the lymph nodes. And patients can be treated with chemotherapy, they can be treated with rituximab, they can be treated with Bruton’s tyrosine kinase inhibitors, but many patients need additional treatment. And so, these are two studies that report on agents that are used for other lymphoma subtypes, other B-cell lymphomas, but trying them out in marginal zone lymphoma.

The first of those is odronextamab, which is a bispecific antibody, an antibody that has one arm that binds to CD20 on tumor cells and another arm that binds to CD3 on T-cells. And this is an investigational agent. There are other bispecifics that are approved. This one is in clinical trials. The take-home here is that of 34 patients with marginal zone lymphoma, the median follow-up of this group of patients was just about a year. The overall response rate was about 80%, and all of the patients who responded had a complete response. With the duration of response not yet reached at 36 months, the duration of response was 72%. And so, this is encouraging.

Bispecific antibodies are an important modality of treatment. This is investigational in the U.S., but shows that marginal zone lymphoma, where we don't so far have approved available agents for marginal zone in the bispecific antibody class suggest that odronextamab might have meaningful activity with again an 80% response rate and complete response rate. These are agents that do have toxicities. They have infection-related risks. They have what's called cytokine release syndrome and inflammatory syndrome, fever, and other issues. So, they're not a free lunch, but this suggests that this agent can be potentially useful and perhaps even this class of agents, or at least this one in particular, might have some future value for patients with marginal zone lymphoma, and these studies are ongoing.

Now, in the 9B selection, loncastuximab is an antibody drug conjugate that is approved for certain types of aggressive lymphoma in particular. And this agent was studied in 22 patients with marginal zone lymphoma, 20 of whom are available for response in the abstract. The overall response rate is 85% with a CR of 75%, and these are ongoing responses in a substantial number of patients, the longest follow-up though is two years, so still more follow up to go. But again, this is another agent approved for different types of lymphoma that could be potentially useful in marginal zone where it's not currently approved at this time. This is also an agent with some toxicities. Again, you can get liver enzyme abnormalities, rashes, some infections, some fluid issues. But that being said, and as I alluded to earlier, there are patients with recurrent marginal zone lymphoma who need other options. And again, these two selections, I think, give you some sense that we might have other agents that are relevant on the horizon.

My next selection, choice 8 in the countdown, is Abstract 565, “Ultrasensitive Circulating Tumor DNA MRD Status Predicts Treatment Failure & Complements PET/CT throughout Treatment for Early and Advanced Stage Classic Hodgkin's Lymphoma”. Dr. Boegeholz is the first author here. And so, many of you may be familiar with the concept of circulating tumor DNA, the idea that tumor cells shed DNA that can be detected through certain assays in the blood and that can be used in some settings to profile the DNA and therefore indirectly profile the tumor. And, in other settings, levels of circulating tumor DNA might correlate with tumor burden and with relapse risk, could be used to essentially assess the quality of a treatment response, potentially predict relapse, or detect a relapse, if it suddenly appears in the blood. And so, these are being explored in a variety of different lymphoma subtypes. They're also being explored in lots of different solid tumors. And this is an analysis of 181 patients with different stages of classical Hodgkin lymphoma, and they were treated in different ways, chemotherapy-based regimens, but also some newer regimens as well.

And the takeaway here is that the circulating tumor DNA seem to correlate with outcome at different time points. And so, if patients had a clearance of their circulating tumor DNA partway through the therapy, that was associated with a better outcome. This is a work in progress, but this highlights the idea that this may be a marker to use to help guide following patients, but also potentially guide therapies.

In Hodgkin lymphoma, we have used interim PET scans, PET scans partway through therapy to either escalate or de-escalate therapy based on how the PET scan reflected a tumor response. But those are not perfect tests and still need room for improvement. So, we and others are exploring the potential of using ctDNA in Hodgkin lymphoma. We have newer regimens that recently demonstrated benefit in upfront Hodgkin lymphoma, including immune checkpoint inhibitors, such as nivolumab. And that's become a recent, I would say, soon to be, if not already standard of care for advanced stage Hodgkin lymphoma patients.

And as we think about questions of can we further de-escalate therapy, give patients less treatment if they're going to do well, or different or more treatment if they're less likely to do well, ctDNA is something that I think has some potential and will be included in many of our clinical trials in the future in different lymphoma settings.

Continuing the countdown, going to the seventh selection. This is a 7A and 7B. 7A is Abstract 3749, “Subsequent Primary Malignancies in Patients with Indolent B Cell Non-Hodgkin Lymphoma Receiving Frontline Bendamustine Rituximab Therapy”. And Choice 7B, Abstract 3009, “Impact of Prior Bendamustine Exposure on Bispecific Antibody Treatment Outcomes in Patients with Relapsed/Refractory Follicular Lymphoma”.

So, the first author on second primary malignancies or subsequent primary malignancies is Dr. Davies. This is a retrospective analysis of a population of patients in Ontario, Canada, over 6,000 patients who received therapy for their indolent lymphoma. Some of them received additional therapy in addition to bendamustine, and these included radiation, autologous and allogeneic stem cell transplant. So, this is confounded a little bit because patients had a number of therapies of different types. And the question here was really focused on patients who got bendamustine-based therapy as frontline or relapse to look at did they get other cancers, what were the rates, and when did they happen.

About 15% of patients got second primary cancers with a median time to diagnosis of 2.36 years. These included lung cancers and blood cancers and other cancers. How much the bendamustine had to contribute to this, I think, is an important issue. These are patients that had a risk of getting one cancer to begin with and therefore may have had risk associations of getting other cancers just by the fact that they have lymphoma as well as the treatment and other factors that might have contributed to this. The takeaway here is not that one regimen or another is better as far as reducing that risk. To me, the takeaway here is that patients need to be monitored for other cancer. And I think that that is a really important issue for all lymphoma patients. You have to think about lung cancers and GI cancers and monitor for blood cancers, breast cancer, et cetera. And so to me, the takeaway actionable item here is really just to make sure that patients are followed and get the appropriate cancer-related screenings because they are at risk for other cancers.

The other things that the authors throw out there is that perhaps less therapy, if we could reduce doses or numbers of cycles of bendamustine, might offer some value. And I think that's an interesting idea, but one that needs to be studied further. So, the main thing is if you've had lymphoma and you have bendamustine or other chemotherapies, you need to be monitored for other cancers.

7B looks at an important practical issue that's come up recently and that is, again, we alluded to bispecific antibody therapies for follicular and other indolent lymphomas. Bendamustine is commonly used. We have approved bispecific antibodies for follicular lymphoma, in particular mosunetuzumab and epcoritamab. And there have been some thoughts that in these T-cell-engaging therapies, as well as with CAR T-cells that rely on strong T-cells, that drugs that interfere with T-cell function or deplete T-cells might be problematic in their effectiveness. And so, this is a study that looked at patients who had received prior bendamustine, which can affect T-cells, and looked at the impact of whether or not that prior bendamustine seemed to affect the efficacy of the bispecific antibody. This is a hard thing to look at because there are various confounders. These patients may have received other treatments, as well. The time from the bendamustine or the other treatments to when the bispecific antibody would be given is an important issue. People that go short times before needing additional therapies tend to have worse disease because they needed another therapy pretty soon compared to patients who went a long time from other therapies. And so, again, it's confounding a little bit in this sort of analysis.

But the takeaway here from these authors is that bendamustine-containing regimens do not seem to confer a negative prognostic impact if it's been given before bispecific antibody therapy. Now that being said, most of the patients in this study had gone more than a year since their bendamustine-based therapy, and many of them had gone a longer period of time. And so, it's reassuring to some extent, that you can give bendamustine and then later give a bispecific antibody, but it probably means a bit that the timing of this issue could also be a factor, that did not seem to make a difference in this study. But again, it was a relatively small number of patients that had a relatively short time interval. And so, there's more there, but I think the practical aspect of this is that if you have follicular lymphoma and you are going to get bendamustine-based therapy or going to use bendamustine-based therapy, and you're worried about giving a bispecific antibody later, you're probably going to be okay, because the time to which that patient is likely to need that bispecific antibody is probably several years later in most cases. And therefore, if in fact there was an impact on T-cells, it seems to be perhaps mitigated by the time difference here. More work to come but reassuring at least at this point.

Next in the countdown is number six. This is Abstract 572, “Interim Analysis Data from the Multi-Center Retrospective Observational Study of Effectiveness, Safety, and Treatment Status of Tirobrutinib in 161 Japanese Patients with Relapsed/Refractory Primary CNS Lymphoma”. Primary CNS lymphoma is typically an aggressive B-cell lymphoma developing in the brain and, if it relapses, can be challenging to treat. It's often treated with combination chemotherapy, sometimes autologous stem cell transplant. Tirobrutinib is an oral Bruton’s tyrosine kinase inhibitor. It was approved in Japan to treat patients with primary CNS lymphoma, and this is a larger analysis of 161 patients from 51 centers in Japan with recurrent primary CNS lymphoma to get more data. And this is a group of patients who had a median age of 70. They have the usual patterns of primary CNS lymphoma; I would say had been treated with the usual things.

And the bottom line is that in this oral drug, the overall response rate and complete response rate were about 77% overall response rate, 55% complete response rate and duration of response being about a year. Toxicity seemed to be similar to other BTK inhibitors. Pretty manageable, I would say. We know that other BTK inhibitors in smaller studies can also have activity in primary CNS lymphoma. But this is, I think, the largest study of a Bruton’s tyrosine kinase inhibitor in relapsed primary CNS lymphoma, showing that this is an agent that has, I think, quite meaningful activity for patients with a high response rate and lasting about a year for patients with recurrent primary CNS disease. So, I would say that this is an advance for patients and something that has some value in certain clinical situations. It may be that other BTK inhibitors also have activity. But again, this is a pretty large series of patients with this one agent in particular.

Next, for Abstracts 5A and 5B, I'm going to stick with the CNS lymphoma theme, and that is to talk about a syndrome called Bing-Neel syndrome. Bing-Neel syndrome is a scenario in Waldenström's macroglobulinemia or lymphoplasmacytic lymphoma. These are indolent lymphomas that have a characteristic profile. Bing-Neel syndrome is a scenario where the tumor cells can involve the central nervous system and these can lead to sensory deficits, motor function deficits, cognitive changes, cranial nerve deficits, other issues. This is a fairly large series of patients, 59 patients from the UK that were diagnosed over about 12 years with Bing-Neel syndrome. The majority of them had a previous diagnosis of Waldenström’s. So, this occurred with a known diagnosis of underlying Waldenström’s. Typically, this was diagnosed with cerebrospinal fluid analyses, lumbar punctures. About half the patients had previous Waldenström's treatment, the remainder had no prior treatment, but most of them had a known diagnosis. This group is not a randomized trial. Again, it was about 59 patients or so. The majority of patients were treated with chemotherapy, methotrexate, cytarabine, rituximab. A smaller number of patients were treated with Bruton’s tyrosine kinase inhibitors, about half the patients ultimately, some as primary therapy, some as consolidation.

And the takeaway here is that the median overall survival was generally pretty good with three-year rates being 93% and, progression-free survival, however, being shorter. But the bottom line was that methotrexate-based therapy was commonly used in this group of patients. Bing-Neel syndrome is a little bit of a moving target. I think we're still sorting out what to treat these patients with. Again, in this series, chemotherapy was commonly used and then Bruton’s tyrosine kinase inhibitors were used. And it seems like the BTK inhibitors, the authors conclude, seem to perhaps give a longer progression-free survival. A small study, it's an uncommon disease complication, but I think this is a useful context as we occasionally see these patients to think about this approach.

Now, 5B gets more specifically at treatment. This is Abstract 1642, “Zanubrutinib is Effective in the Treatment of Patients with Waldenström's Macroglobulinemia and Bing-Neel Syndrome”. And this is a retrospective study of 11 patients from 10 Spanish centers and highlights a fairly typical presentation of this entity. Interestingly, about half of these patients, it was their initial presenting feature, half had a known diagnosis. Nine of the eleven patients had zanubrutinib, the Bruton’s tyrosine kinase inhibitor, as their first line therapy. The others had it as a later therapy.

The takeaway here was that the overall survival was reasonably good with these patients, going out at least a year or so. Again, there's not a ton of follow-up, but about 80% of patients were alive in the ballpark of close to a year. And the overall response rate was about 75% or so. And so, this suggests that the BTK inhibitors may be useful therapy for primary or relapsed Waldenström’s in the setting of having Bing-Neel syndrome. And so, small study, but it’s something to suggest that this may be a useful treatment.

Now, we'll move to abstract number four. This is Abstract 1667. The first author is Dr. Kuczmarski. It's entitled “Potential Delayed Immune-Related Adverse Events in Patients Treated with Frontline Pembrolizumab + AVD for Classic Hodgkin Lymphoma”. As we alluded to, the combination of chemotherapy and immune checkpoint inhibitors are being used more and more in classical Hodgkin lymphoma. Nivolumab, another checkpoint inhibitor, has been combined with AVD in a randomized trial showing a clear benefit. And I think will be used more and more, at least in advanced stage and possibly also earlier stage Hodgkin lymphoma. And what this study did was looked at 50 patients in an investigator-initiated clinical trial of pembrolizumab plus AVD.

And the important takeaway here was that nine of the 50 patients, or 18%, experienced a potential delayed immune-related adverse event. These were predominantly grade 1, but two of them were grade 4. The majority of these adverse events were endocrinopathies with four cases of hypothyroidism, two of hyperthyroidism, one case of adrenal insufficiency. And there were also a handful of other things including pneumonitis, arthritis, and uveitis.

It'll be interesting to see the larger studies with more follow-up, but in this reasonably carefully analyzed small, essentially single-institution study, about 20% of the patients had distinct delayed adverse events, and the median onset of these was 163 days after completing therapy. And if I do my math right, we're going out five or six months after completion of the therapy. And so, we're commonly looking for these adverse events while we're treating the patients. The patient is done, we say, "Okay, we'll see you in several months," important to keep in mind that they do need to continue monitoring, particularly for hypothyroidism or hyperthyroidism, as well as for other autoimmune processes that can happen. So, I think this is an important practical point to keep in mind as we think about patients getting treated with immune checkpoint inhibitors, we do need to continually follow them for immune-related side effects -- even months and probably even years after they complete therapy.

Next, we'll move to abstract number three in the countdown. This is Abstract 235. Dr. Lewis is the first author. This is entitled “Ibrutinib-Rituximab is Superior to Rituximab Chemotherapy in Previously Untreated Older Mantle Cell Lymphoma Patients: Results from the International Randomized Controlled Trial called ENRICH”. And this is a study that looked at chemoimmunotherapy, either bendamustine-rituximab or CHOP-rituximab, versus using first-line ibrutinib with rituximab as initial therapy, asking the question whether or not a non-chemotherapy-based, BTK-driven approach with rituximab could be superior to chemoimmunotherapy.

This was 397 patients, roughly 200 getting either chemo-based therapy or ibrutinib-based therapy, that showed that there was a benefit in progression-free survival that was superior with the use of ibrutinib and rituximab, with a median progression-free survival being 65 months versus 42 months.

Now, there are some important takeaways here. These patients could either get CHOP-based therapy or bendamustine-based therapy. And I think an important caveat here is that the difference seemed to be favoring ibrutinib much more in the CHOP-based therapy group. The bendamustine-based therapy group did not differ quite as much from the ibrutinib-rituximab. And so, I think that's going to be an important bit of information to look at that subset of patients. Is there really a benefit of IR versus BR, which is more commonly used? However, this does suggest that IR offers benefits versus chemoimmunotherapy and could be considered a standard of care for frontline therapy. I think the subsets of chemotherapy and how they look will be important. Also, keep in mind that those that get chemoimmunotherapy and progress can get ibrutinib or can get a different BTK inhibitor. We don't know yet what the best therapy is and the effectiveness of chemotherapy or other things in patients who have received ibrutinib-rituximab, or another BTK inhibitor as part of upfront therapy. So again, what's the second line therapy going to look like? What's the longer-term outlook with overall survival? Those are things that are going to be interesting to follow in this study. But I think it's an important randomized trial that may change the standard of care for some patients with mantle cell lymphoma.

Next in the countdown, we're going to go to number two. This is a little bit different abstract, but I think warrants some attention. And I give kudos to Dr. Maclean and colleagues for this abstract, Abstract 2267, “Toxicity Outcomes in Phase I Lymphoma Trials: Variable Reporting with High Use of Minimizing Language in Published Abstracts at International Conferences”. This is an analysis looking at specifically phase I lymphoma trial abstracts at seven international conferences between 2022 and 2024, including the ASH Meeting as well as other national and international meetings. The abstract looked at 326 presentations across the spectrum of lymphoma and focused on toxicities and how toxicities were categorized. And suffice it to say that there was a lot of heterogeneity in how toxicities were described as far as grading of adverse events. Whether or not they were related to the treatment or not, whether or not they required dose modifications or discontinuations, that was in a minority of patients. And really, I think, this was also perhaps heightened in cell therapy-based approaches like CAR T-cells.

The other interesting thing that a number of us have noticed is that the concluding remarks often describe the regimen is tolerable, or safe, or manageable, or acceptable. And this highlights, I think, the imprecision of this term. What are the definitions of this? It's in the eye of the beholder. I probably have been guilty of this at one point or another, or maybe more points along the way. We often are not precise enough in our discussions and descriptions of toxicities and in the tolerability or toxicity of a regimen. And I think this highlights that we need better communication, better transparency, as the authors state, and I think more precision. What is something that is tolerable or manageable is really, as I said, in the eye of the beholder and probably a judgment that needs some sort of basis for it, some data behind it, some quantifiable rather than qualitative nature, that can really put this into context so that patients and physicians and families can really understand is this a regimen that I want to take or that I would be okay taking rather than just these broad brushes. So, I give kudos to the authors to highlighting this issue and hopefully we can make some progress around this going forward.

Finally, the number one cited abstract for this year's Leonard List at ASH 2024 is led by Dr. Casulo and colleagues. This is Abstract 1652, “Outcomes in Early Relapse of Follicular Lymphoma Versus Early Histologic Transformation Following First-Line Immunochemotherapy in Follicular Lymphoma”. Dr. Casulo and colleagues established that patients who progress within two years or have POD24 of their initial treatment have a less favorable outcome of follicular lymphoma and are at higher risk of dying of their follicular lymphoma.

However, it's been pointed out that transformation to an aggressive subtype is a major driver of these less favorable outcomes for the population as a whole. It turns out that a subset of patients with POD24 and histologic transformation exist, but some of the patients that progress early do not have histologic transformation. And so, this is an analysis of 1,100 patients, about 300 of which had POD24. And it focuses on the issue of the group of patients that had either biopsy-proven follicular lymphoma, no biopsy, or an uncertain biopsy, where the 20% of these 20% who had biopsy-proven histologic transformation.

And the takeaway here is that those patients who had an early relapse are a heterogeneous group, but the group of patients do significantly less well if they have histologic transformation. That's a group that needs further analysis. And then, the other group, those that progress within 24 months but do not have histologic transformation are a group that really are intermediate, but I think this abstract, and I think it'll be interesting to see the details of the presentation, really highlights the fact that POD24, which commonly gets reported on and cited, is really a heterogeneous group and probably the devil's in the details as to what we expect out of these patients. Histologic transformation will be a big driver of that and the presence or absence of that, I think, probably puts patients in at least two different categories. And again, this data will give more details with the idea that the POD24 group that relapsed with follicular lymphoma, perhaps an intermediate group compared to the POD24 group that has transformation, and that's a group that really is the biggest group that has an unmet need and further need for interventions and new strategies.

All right. We've counted down the 10 Leonard List selections for ASH 2024. I'm now going to give you a few bonus rapid selections. Thank you for joining the podcast and getting a little more detail. And so for your extra time and effort and interest in this, we're going to give you five bonuses.

So, the first bonus, number one is abstract 4406, “Real World First Line Treatment Strategies and Outcomes in TP53 Mutated and Unmutated Mantle Cell Lymphoma”. This is Dr. Wang and colleagues, looking at large group of mantle cell lymphoma patients, 645 patients. And this study focused on prognostic issues and, in particular a smaller subgroup of patients that has p53 mutations. We know that that's a minority of patients with mantle cell lymphoma. And that is a group of patients, however, that has a less favorable outcome if they have mutations and does less well with chemotherapy.

This retrospective analysis gives a lot more granularity than we had before. A lot of these data came out of smaller, single-arm studies. And so, this is a large study. And basically, what this shows is that the outcomes are different. The overall survival is different, but that for p53-mutated patients, the outcomes are still quite meaningful. There's a group of patients that lives years, in fact, over eight years in many cases, not as favorable as those that do not have a p53 mutation, but also not necessarily dismal, which is good news. And I think that the other thing that's important here and the analysis looks at in more detail is that chemoimmunotherapy and BTK inhibitors are really part of the therapy for patients with p53 mutations. But this study even calls into question a little bit the fact that you have to give a BTK inhibitor in frontline therapy for a p53-mutated patient. I think that these are interesting data, and I think there's a lot of devil in the details, and I would say from the abstract I'm not personally quite sure what to do with this. But clearly, I think one of the things that comes out of this is that, given newer therapies, particularly BTK inhibitors and other approaches, we are having better outcomes for patients with mantle cell lymphoma, both those without p53 mutations and those with p53 mutations.

So, I think that this reiterates that p53 mutations matter, but also gives a little bit of hope that we are making progress for this group of patients, and I think documents some of that progress, even though there's more work to do. This is one that I'm looking forward to more detail on to see if there's anything here when it's presented that gives more details as to how we should consider treating these patient populations. So, I'd encourage you to learn more about that. At this time, I just have the abstract, but I think that's an abstract I'm going to be paying attention to in follow-up.

All right. Bonus 2A and 2B relates to the POLARIX study. This is a study that is known to many of you, I'm sure, that for many patients has altered the therapy for diffuse large B-cell lymphoma. The POLARIX study is a study that looked at R-CHOP versus substituting polatuzumab, the antibody drug conjugate against CD79b for vincristine and R-CHOP. It was a randomized trial. And that study has been presented in the New England Journal of Medicine and elsewhere, showed a progression-free survival benefit, but not an overall survival benefit to the substitution of polatuzumab for vincristine. So, Pola-R-CHP has been now widely used for a number of patients as upfront therapy with diffuse large B-cell lymphoma.

So, Abstract 469, the “Five-Year Analysis of the POLARIX Study” is led by Dr. Salles and colleagues. And again, to remind you, this is a large study. It's been presented, but basically includes a global intent to treat population, over 800 patients treated with each of Pola-R-CHP and R-CHOP, the five-year progression-free survival was 64% versus 59%, so with more follow-up. And the overall survival is quite similar. There was a numeric difference between the two arms, but not a statistically significant difference. And so, at the end of the day, I think that this is reassuring that the outcomes are holding up, I would say, that there is a PFS benefit difference, but no overall survival difference, probably because we have additional treatments for relapsed large cell lymphoma, which have some degree of effectiveness. And so, I would encourage you to take a look at this, mainly because of the fact that this is a regimen that is now very commonly used in practice. And so, it's good to have additional five years follow-up data.

The bonus 2B here is Abstract 652. I would call my companion to this, and this is the “Predictive Value of Cell-of-Origin Subtype by Hans Algorithm in 718 Patients With Large B-Cell Lymphoma Receiving Polatuzumab Vedotin”. Dr. Cliff and colleagues generated this abstract. This is important because the initial POLARIX study suggested in a subgroup analysis that the non-germinal center or activated B-cell subtype of diffuse large B-cell lymphoma seemed to do better with polatuzumab swapped in for vincristine, but that in the germinal center subtype, the difference seemed to be less pronounced. This is a retrospective multi-center observational study of a large number of patients, over 700 patients who received this regimen. And the takeaway here is that the authors conclude that the cell of origin classification by Hans, which is an immunohistochemistry algorithm to identify the non-germinal center subtype, suggest that the benefit of polatuzumab seems to be bit more supportive of outcome here, meaning that the cell of origin subtype may be useful in choosing to use polatuzumab in the bottom line here. And so, this is an interesting set of additional data, and I look forward to seeing the details of this abstract, but basically will give us more information that perhaps we should consider focusing our polatuzumab use in the non-germinal center subtype. This study suggested that the non-germinal center subtype had higher overall response rates and CR rates in the non-germinal center compared to the germinal center subtype, suggesting that perhaps that may be the group with the most difference.

And so, my takeaway is that if you see a patient with non-germinal center subtype, you certainly should think hard about incorporating Pola-R-CHP as your upfront regimen in diffuse large B-cell lymphoma, and in the germinal center subtype, perhaps the data are not as compelling to include polatuzumab over vincristine.

Our third bonus abstract is a little bit different. It's a leukemia rather than a lymphoma. This is Abstract 979, “A Prospective Multicentric Phase II Randomized Controlled Trial Comparing the Efficacy and Toxicity of Methotrexate to Cyclophosphamide in Large Granular Lymphocyte Leukemia”. So, LGL leukemia is a clonal T Cell or NK cell disease, where we see often neutropenia, anemia, autoimmune diseases such as rheumatoid arthritis, and a clonal population of these lymphocytes associated with these findings. So often, these patients have autoimmune disease or other cytopenias that need therapy, and it's a relatively uncommon disorder and there are lots of different expert guidelines, including from Dr. Lamy who is the lead author of this study, suggesting that there are a number of different options, but the expert guidelines don't necessarily compare them in a robust way because there are relatively few comparative studies.

So, this was a multi-center study that looked at an open-labeled randomized trial comparing oral cyclophosphamide, one of the commonly used treatments, and oral methotrexate. It's really a four-month therapy, and then looked at continuing up to a year typically, if they responded or changing therapy, particularly adding receiving ciclosporine, if they were non-responders. And there's some details of this which will be interesting, but the takeaway is comparing methotrexate to cyclophosphamide.

And the bottom line of the study suggested that cyclophosphamide induces a better response to methotrexate in terms of complete response and overall response rate after four months of treatment, whereas the toxicities were quite similar when you look at infections, cytopenias, and other issues. And so, this provides some data. We'll look at the details. It's a small study, but hard to do large studies in this particular setting. But the overall response rate was higher in the cyclophosphamide group compared to the methotrexate group with similar toxicity.

There are also a number of different molecular analysis that are being looked at. The other details about the patient population given the heterogeneity that will be interesting, but I think this will be important potentially to help guide how you approach these patients in practice.

Next, bonus abstract number four is Abstract 782, entitled “Travel Burden and Travel Costs of Bispecific Antibodies in Patients with Relapsed/Refractory Diffuse Large B-cell Lymphoma and Relapsed/Refractory Follicular Lymphoma”, led by Dr. Huntington. This was a study done by a group including investigators at Yale and Fox Chase, as well as Genentech, and an economics firm, Medicus Economics, and using an economic model. And I don't have huge expertise in the economic model, so I'm not going to really critique it one way or another. But I think this is an interesting analysis that highlighted for me, and the authors are comparing mosunetuzumab and epcoritamab, and making the point that there are some differences between the two agents, I think, in part, attributable to the number of doses that patients need.

But to me, the takeaway is just the data and the analysis, and this looked at patients who compared and connected the travel burden based on the one-way trip from the patient's home to where they got treatment. So, looking at the actual distance traveled and therefore time, and looking at productivity loss based on wages, so a fairly detailed analysis here. The takeaway here for me is just that it highlights rather than comparing the two antibodies, which I'm not going to do in this setting, although you would expect that the agent that needed more therapy took more time, not a surprise. But it highlights the travel burden and costs and time for patients to get these treatments. And at the end of the day, it adds up for a large group of these patients, upwards of 3,000 and 4,000 miles of driving and travel, and between 50 and 80 hours of time in travel. And so, I think, my takeaway is just that this is a factor that is interesting and important to our patients and something we don't take into account and probably we should be thinking about a little bit more. Taking 50 or 80 hours or longer out of work or other things you have to do if you're a family member or a patient, and the cost of $2,000 and $3,000 in some cases for patients to travel, this is a burden of care that we don't always think about in our practice and probably should be paying some attention to.

Finally, the last bonus abstract here for you in the Leonard List for ASH 2024, bonus five, is Abstract 571 entitled “Prognostication and Treatment-Related Outcomes in Secondary CNS Involvement of Large Cell Lymphoma”, led by Dr. Alderuccio. This is a large multi-center international group that collected data from 35 centers over 20 years and identified 1,100 patients with secondary CNS lymphoma and gives a lot of detail on these patients, whether or not they progressed or developed their secondary CNS lymphoma at the time of diagnosis or whether they relapsed in the CNS. This gives some interesting data around median progression-free and overall survival. It seems like the patients who had secondary CNS lymphoma and presented with it did better than those who relapsed with it. So, I think to me that might give a message that we should be looking for it a little bit more, at least in high-risk patients, and dealing with it upfront rather than at relapse.

And this is, I think, in conclusion, really the largest analysis of this group of patients, and it'll be interesting to see the details of this abstract and characteristics of these patients. It also suggests that patients who got autologous stem cell transplant as consolidation associated with better outcomes, both if it was de novo or a relapse disease. That's in some ways not a surprise because these patients had chemo-responsive disease, could get to a transplant, and were fitter, so you would expect that they did better. But I think this is a very large, international, multi-center series of these patients that provide some interesting data that characterizes this group of patients and may be useful as we think about how to approach them in the future. Now as we have newer agents, as we've talked about BTK inhibitors for certain CNS-involved lymphomas, as we think about CAR T-cells and bispecifics, I think these will be interesting data and interesting scenarios to see can we further improve outcomes for this group of patients using some of the new tools we have.

So, that brings us to the end of this session. Thank you for hanging in there and listening to the 2024 ASH Leonard List. I think, as you can see, there are going to be lots of data. There were a number of other abstracts that I thought about and didn't choose. There's even a Plenary Session abstract relating to improving CAR T-cell therapy in lymphoma, which I think will be very interesting to see and hear what people think about that. A lot happening, a lot to be encouraged about for patients. And I'm really looking forward to ASH 2024. These are, I think, a number of studies that clearly impact the field, may impact therapy. And as always, we come away from ASH and the abstracts and presentations we see with new ideas for research directions as well as opportunities to help patients that we see in our practice.

So, thank you so much for joining us for this episode. I want to invite you to download, subscribe, rate, and review CancerCast on Apple Podcasts, Spotify, or online at weillcornell.org. We also encourage you to write to us at cancercast@med.cornell.edu with questions, comments, and topics you'd like to see us cover more in depth in the future.

That's it for CancerCast, conversations about new developments in medicine, cancer care, and research. I'm Dr. John Leonard. Thanks for tuning in.

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