Dr. John Leonard: (Host) Welcome to Weill Cornell Medicine Cancer Cast, conversations about new developments in medicine, cancer care, and research. I'm your host, Dr. John Leonard, and today we will be talking about my most interesting 15 lymphoma related abstracts that will be presented at the 2023 Annual Meeting of the American Society of Hematology.  

This is something that I've done for the last six years or so, and I've termed it LeonardList, and it's been something that's been quite fun, and I've had friends in the community that have heard about this and give me feedback on this list of interesting abstracts, and so it's lot of fun for me to be able to present this to you.  

The American Society of Hematology is really one of the largest international meetings. ASH is the acronym that's used. ASH is the society that hematologists belong to, those who work in blood disorders, basic research, clinical research, outcomes research, and clinical care.  

And it includes malignant hematology, meaning tumors and blood cancers as well as other blood disorders, and basic science. And so this is a meeting where several thousand hematologists come and research is presented.  

There's an educational program, there are research presentations and various other talks and gatherings to really try to move the field forward and educate the public. And so different investigators, different research teams submit their research in what's termed an abstract.  

Some of these abstracts are published. Some are presented in what we call poster form, where you stand in front of a poster board, essentially, and present the work. Some are presented orally in an auditorium sort of fashion. And then the most significant just handful are presented in what's termed the plenary session in a very large auditorium that the whole group of attendees joins.  

For about six years now, I have chosen 10 abstracts relating to lymphoma that I found to be interesting each year. I have typically been counting them down one at a time in the 10 days that are preceding the ASH meeting and commenting on them and highlighting them on Twitter.  

I have provided this overview with a little more depth over the course of a podcast episode. And I've also added in five additional kind of bonus abstracts to give you a little more information, so hopefully you find this interesting. And I tried not to always pick the obvious choices that everyone's going to see, but occasionally try to highlight a few things that I think are relevant or interesting or thought-provoking as well as some that are practice changing.  

I hope that one way or another, you'll give me some feedback, and I'm also always very happy to hear other suggestions and other ideas or other aspects of these abstracts and studies that perhaps I didn't appreciate or have a different view.  

So without any further ado, I'm going to go ahead and count down first the 10 choices then I'll come to the five bonus selections after that.  

So number 10 is abstract 4399. This is entitled “Early Stage Follicular Lymphoma: Learnings from the Final Analysis of the Multicenter Phase II, FIL”, that's Fondazione Italiana Lymphome, my Italian is not very good there. Also called the MIRO trial. And this is focused on new approach to combine local radiotherapy and what's termed MRD or Minimal Residual Disease Driven Immunotherapy. And the first author is Pulsoni and colleagues. And this is, as the name implies, a group of investigators, almost all from Italy.  

So the concept here is that follicular lymphoma is a chronic, indolent, slow growing lymphoma. Most patients have advanced stage disease that is in multiple locations. But somewhere around 10 to 20 percent of patients will have what we call early-stage disease, where it's localized in one area. 

And there's some debate as to how you approach these patients. Historically, they have been treated with radiation therapy, and many of these patients can have long term remissions over decades and potentially even be cured based on some perspectives on that, but they can often also relapse, unfortunately. 

And so the background of this is that since maybe 40 to 50 percent of patients might have long term remissions and 50 percent might not, the question is why do those patients relapse? What can we do to predict it and potentially choose therapy? You might not give radiation or you might give something else if you knew someone was more likely to relapse versus if you thought that someone was not likely to relapse, maybe you would stick with radiation alone or approach them a little bit differently. 

So a lot of ideas and to try to predict who truly has local disease, and the concept of this study is to essentially use what's termed MRD, a molecular analysis, to use what's called nested PCR, to basically look at the blood or the bone marrow or both to see if there's molecular evidence of lymphoma outside of the local area. 

And in those cases where patients had detectable disease or became detectable disease at this minimal disease molecular level, additional therapy with an anti CD20 antibody called ofatumumab was administered in this study. 

And the bottom line of this, this was about 106 patients. They had a median age in their mid 50s. They had generally low risk disease. And the net of this study was basically that this MRD status was fairly useful in being able to predict did a patient have disease outside of the radiation field and therefore did these patients need additional therapy because local radiation aimed just to one part of the body was less likely to eradicate the disease. 

And what they did in this study was if they had MRD positive disease, meaning molecular evidence outside of the area, they provided this additional therapy. I highlight this abstract not because I think this is necessarily the best approach. One can still debate which way to treat locally involved follicular lymphoma patients. 

One can also debate what's the value of giving therapy early versus late in somebody who has some molecular evidence of disease outside of the radiation field. One can even debate, is there value of radiation itself in the long term? Because there are lots of ways one can approach this. But I think this is a step in the direction of using newer tools, whether it's MRD in this case -- or particularly in the future, potentially even circulating tumor DNA – as a way to better stratify to characterize patients with limited stage follicular lymphoma, a group of patients that perhaps radiation is a good choice if they truly have localized disease, but it's probably not a good choice if they don't. And so, the idea that you can better tailor therapy, avoid therapy, or choose an appropriate therapy for someone based on these molecular markers is interesting. 

I don't think this is a definitive study, but I think it does give us some information as to the potential approaches one might be using, and I think in the future, the idea of approaching these patients in different ways will be quite interesting, remembering however that this will require long term study because these are early-stage follicular lymphoma patients who are likely to have a very good outcome in their big picture because they have a good prognosis by the fact that they have limited stage disease. 

So, that is Leonard list number 10 for this year. We'll now move to my ninth selection for ASH 2023. This is abstract number 4456, entitled “Fertility and Gonadal Function After First-Line Treatment with Nivolumab AVD in Hodgkin Lymphoma Patients, an analysis from the Phase 2 GHSG Nivahl Trial”. 

And this is a group from the German Hodgkin Study Group led by Dr. Broekelmann and colleagues. And the value of this is that it analyzes 109 patients with early- stage unfavorable Hodgkin lymphoma, and a large proportion of these patients received in one fashion or another nivolumab, the immune checkpoint inhibitor, and AVD chemotherapy, adriamycin, vinblastine, dacarbazine. 

There are other studies now, which we'll come to later that show that NAVD, nivolumab based therapy with AVD chemotherapy may become, or is in the process of becoming, a standard upfront therapy for a large percentage of patients with at least advanced stage Hodgkin lymphoma. 

And the question that comes up in a disease that affects younger patients in particular women who have fertility concerns in many cases and may not be able easily to do fertility preservation, what are the outcomes as far as fertility? Now, we know that with a previous standard therapy, ABVD, fertility seems to be quite good in the long term. 

And the net of this study, I won't get into the details, but they highlight various hormone levels and pregnancy rates, all of which can be confounded by various things i.e. do patients desire pregnancy, what is their state to begin with in this regard. But the bottom line of this is that it appears that Gonadal function is preserved in the majority of both female and male patients, and really this is somewhat reassuring that there do not appear to be major impacts on fertility with this regimen, which is obviously very important, very reassuring to patients. 

Admittedly, more patients need to be studied with longer follow up, but it does provide reassuring that our general impression that this regimen should be relatively good with respect to fertility preservation. So more to come, but again, important and valuable practical information, particularly for young patients who desire fertility preservation and are being treated with this new regimen for their initial treatment of Hodgkin lymphoma, particularly advanced stage. 

Now we'll move to Leonard List No. 8 for ASH 2023. This is Abstract 1031. First author is Saidy and colleagues from Berlin and elsewhere primarily in Europe. And this is entitled “Efficacy of CD19-Directed CAR T Cell Therapy in Patients with Primary or Secondary CNS Lymphoma - an Analysis of the EBMT, (that's the European BMT Network Lymphoma Working Party,) and the Gocart Coalition”. 

This is focused on patients that received CAR T cell therapy, which we know is an important therapy for patients with recurrent aggressive lymphoma, as well as other subtypes of lymphoma. And we know that some of these patients can have central nervous system involvement. Others may have primary central nervous system involvement. And in both of these cases, we know that the prognosis can be quite challenging. We have small reports out in the literature that patients with central nervous system involvement can respond to CAR T cell therapy. 

And so this is a fairly large series of patients. It's 88 patients, 10 of whom had primary central nervous system lymphoma and 78 had secondary central nervous system lymphoma. They had a median age of 63, and about two thirds of them had three or more prior treatment lines of therapy, with also about two thirds having disease refractory to at least one prior line of therapy, and about a third of them receiving previous autologous stem cell transplants. 

This is a group of patients with fairly recurrent resistant disease, either primary or secondary CNS lymphoma, and again they were treated either with adaptogen siloso, or tegen siloso, two of the agents available. 

And the net of this was that the overall survival of this group of patients at two years was 47 percent. The progression free survival was 33 percent. And again, if patients responded, not surprisingly, they tended to do better. 

I think this is larger experience than we've seen in the literature for the most part before, but very helpful to suggest that these patients with central nervous system involvement and previous treatment can have a reasonable chance, somewhere around 30 to 35 percent chance of doing well for two years or longer with CAR T-cell based therapy.

This is encouraging and I think the authors even suggest that this approach CAR T cell therapy with patients with recurrent large B cell lymphoma and CNS involvement may be the preferred treatment option. I think that may be open to still some debate, but it is encouraging that these patients could do well with this approach, and again, helps to potentially inform practice for this group of patients that generally has a less favorable outcome. 

Next, we'll move to Leonard List No. 7 of ASH 2023. This is from Dr. Soumerai of Mass General Hospital and colleagues. Abstract 3040, “Infection Outcomes and Hypogammaglobulinemia in Patients with Non-Hodgkin Lymphoma Treated with Immunoglobulin Replacement Therapy”. And this is a retrospective longitudinal observational study looking at patients with reduced serum immunoglobulin G levels -- IgG levels, that are low. 

And this is a group of patients we know that this can occur, either for a variety of reasons after lymphoma and lymphoma therapy, and infections can be a major cause of morbidity and mortality in this patient population. This study looked at over 13,000 patients and found just over 600 patients who received immunoglobulin replacement therapy over the follow up period. 

And the bottom line is that immunoglobulin replacement therapy was chosen by the physicians and patients for various reasons. So there may be some biases in that selection, but that being said, in this 600 patient group, the patients who received immunoglobulin supplementation, this was associated with lower rates of hypogammaglobulinemia, not surprisingly, because they were given gammaglobulin, but importantly, lower odds of infection, severe infection and antimicrobial use over about a three-month period after initiating this therapy, and the odds ratios were in the range of about 0.5. 

And so, this, I think, really suggests the value of intravenous immunoglobulin supplementation for patients with immunoglobulin deficiency in the setting of lymphoma and lymphoma therapy. 

And again, it's not a randomized trial, but it does certainly suggest that for some patients this can be quite valuable with respect to these important and sometimes debilitating and significant life-threatening complications. 

Next, we'll move to Leonard List's choice number six. This is abstract 2344, “The Glass Wall: Gendered Authorship Disparities in CD19 and BCMA CAR T Cell Clinical Trials for Lymphoma and Myeloma”. This is from Dr. Khaliq and colleagues from the University of Kansas School of Medicine and otherwise. And as we know, there are a variety of different literature sources that suggest that women are underrepresented in hematology and oncology. 

Women make up about a third of hematologists, according to data from 2021. And this study seeks to look at authorship in Clinical Trial and Clinical Research, and the authors focused on 13 pivotal trials that led to the approval of CAR T cells for acute lymphoblastic leukemia, lymphoma, and myeloma, published between 2017 and 2022.What they looked at was the number of female authors, the number of lead female authors as defined by first, second, or last authors in the publication, and the ratio of all authors to female authors. On the net of this was that of about 367 authors,  about a hundred were female, so this correlates to about 29 percent of the authorship being female. 

That roughly correlates to the percent of female hematologists in the community broadly. The only study with female authorship was a pediatric study. All of the others had more than 50 percent male authorship. About 50 percent of the studies had females in a lead author role, and interestingly, 6 out of the 7 studies were published after 2021. 

I think the bottom line of this study suggests that there is improving gender equity in authorship in more recent publications since 2021 and in certain research areas, particularly pediatric hematology/oncology. And so, I think this is important information, perhaps encouraging in some ways, but also suggesting that there may be more work to do to improve equity amongst our research force and caregivers in hematology and oncology, and obviously highlights the importance of providing leadership and authorship opportunities to groups that may otherwise be underrepresented. So, I think this is thought provoking and very important information and something that our field should really continue to emphasize and track as we look at the literature and look at the workforce of those working in our field. 

Next, I'll move to Leonard List No. 5 from the American Society of Hematology Meeting 2023. This is Abstract 1760, “CD79 Expression Is Associated with Cell-of-Origin and Outcome in Diffuse Large B-Cell Lymphoma”. This is from Dr. Naoi and colleagues from Japan primarily and Canada. And this is focused on the expression of CD79 in patients with diffuse large B cell lymphoma. 

Why is this relevant? CD79B is the target of polituzumab vedotin, which is an antibody drug conjugate which has improved the progression free survival of patients with diffuse large B-cell lymphoma when polituzumab has been substituted for vincristine in the RCHOP regimen. However, the importance and the details and the biology of CD79B remain under exploration. 

And this is particularly interesting or this theme of research is interesting because of the fact that in the Polarix study that looked at polituzumab, there seemed to be a potentially differential effect in a subset of patients with diffuse large B-cell lymphoma based on cell of origin, in particular, the activated B cell subtype. 

The takeaway of this study, and I don't think this is definitive, but it does raise an important issue, is that the expression of CD79B low cases, meaning low expression of CD79B was seen in an enriched fashion in patients with ABC DLBCL. This is one of the cell of origin subtypes, although we now recognize that the classification of DLBCL is getting much more complicated and subdivided. 

And this raises the idea that, again, CD79B expression patterns differ among different subtypes in DLBCL, and therefore this may explain or relate to a possible differential effect of polituzumab and value of polituzumab in different subsets of DLBCL.

So this is not, in my view, a definitive study, and in fact, lower expression of CD79B was seen in the ABC subtype where the drug polituzumab might be more potentially valuable at least in some analyses. So it doesn't explain the whole story, but it does highlight a connection between the target of the drug and potentially at least some connection to the efficacy in a patient subset. 

So more work to do, and I think we're going to see other studies looking at this in more detail as we tease out where polituzumab may be helpful in DLBCL, and I think this is just one example of work in this area that is worth paying attention to going forward. 

Next, we'll move to Leonard List No. 4 in ASH 2023. This is Abstract 185. Lecutamab. This is a new agent for me, although maybe some of you have already heard of this agent. This is an antibody that's being explored in relapsed and refractory Sezary syndrome, results from the Tellomak Phase II trial. This is from Dr. Bagot and colleagues from Paris and also elsewhere in the U.S. and Europe primarily. 

Cutaneous T cell lymphoma (CTCL) is uncommon but important form of non-Hodgkin’s lymphoma and Sezary syndrome is less common, aggressive, advanced type of CTCL commonly associated with circulating tumor cells in the blood and lymphadenopathy as well as erythroderma. One of the things about CTCL and Sezary syndrome that is interesting is that it tends to express something called KIR3DL2. 

This is a killer immunoglobulin like receptor that's seen in the vast majority of patients. And so, Lecutamab is a first-in-class monoclonal antibody, according to the authors, that targets, KIR3DL2 expressing cells using ADCC and phagocytosis. And so this is a study that included 56 patients with Sezary Syndrome in the first cohort. 

They had a median age of 70, a median of six prior therapies, so fairly advanced stage disease. About two-thirds of them had a high percentage of erythema across almost all of their body surface area. And the interesting part of this study was that the overall response rate in this fairly poor prognosis group of patients was 37%. A couple of patients had complete responses and blood overall responses were seen in about half of patients. A clinical benefit rate CR plus PR plus stable disease was 87%, with a median progression free survival of about 8 months. And the tolerability profile is not well described in the abstract, so we'll see more about this in the presentation.

But it does suggest that this might be a useful agent given the results with regard to efficacy. We need to see the tolerability in more detail for patients with what seems to be fairly advanced and recurrent Sezary syndrome, which can be quite challenging. So an interesting, relatively new agent that may be worthy of attention, albeit in this relatively rare form, but important and challenging form of cutaneous lymphoma. 

Number three in Leonard List ASH 2023, presentation is Abstract 181, “Novolumab AVD is Better Tolerated and Improves Progression-Free Survival Compared to BVAVD in Older Patients (Aged 60 or More) With Advanced Stage Hodgkin Lymphoma Enrolled in SWOG S1826”. So, this is presented by my colleague from Weill Cornell, Dr. Sarah Rutherford. This abstract is a subset of patients from the Southwest Oncology Group's intergroup study, S1826, that randomized patients with advanced stage Hodgkin lymphoma to nivolumab, the immune checkpoint inhibitor I alluded to earlier, plus AVD versus brentuximab vedotin AVD. And that was a positive study, both with regard to progression free survival and had some benefits with regard to tolerability. 

So Dr. Rutherford herein reports about a 100 patients, 60 or older, enrolled in this study, about 50 of whom received NAVD, nivolumab AVD, versus another 50 or so received brentuximab vedotin AVD. And the bottom line was that nivolumab AVD was better tolerated. There was less febrile neutropenia. There was less sepsis and infection, less peripheral neuropathy, and these were some of the major adverse events, although there were some autoimmune events, not surprisingly, in those who received nivolumab. But in general, the tolerability was better for NAVD and importantly, the progression free survival was superior with NAVD. The one-year progression free survival was 93% versus 64% favoring nivolumab AVD. and there were fewer deaths on the nivolumab arm, two deaths versus seven deaths. Five of which were due to infection and sepsis in the BVAVD arm. And so I think this provides particularly strong rationale based on this subset analysis to consider nivolumab AVD as a good treatment for patients with advanced stage Hodgkin lymphoma who are age 60 or greater. 

We'll now move to number two of Leonard List ASH 2023. This is Abstract 169, “Plasma Circulating Tumor DNA, (or ctDNA), as an Alternative to Tissue DNA for Genotyping of DLBCL” Results from the Polarix study”. 

So I referred to the Polarix study earlier. This is the study of RCHOP versus RCHP plus polituzumab, the anti CD79B antibody drug conjugate. This is an analysis led by Dr. Jardin and colleagues from France and elsewhere in the world. And what this study did was to look at circulating tumor DNA. The analysis of this study looked at the prognostic value of ctDNA at various time points. 

The goal of this particular analysis was to compare the mutation landscape and molecular subtyping of DLBCL of plasma ctDNA versus tissue DNA using the lymph gen classifier. And the idea here is that this is a classifier that analyzes DLBCL into different subsets, groups that have different molecular characteristics and, in some cases, different outcomes. 

And the takeaway of this study is that the ctDNA mutational profiling was useful in characterizing the subset for patients and that this was quite concordant with what was seen in the primary tumor tissue. And so I think this is valuable information because these findings support the use of plasma ctDNA as a way of getting the material to subclassify patients with DLBCL and I think this will be an important tool in the future as we try to design clinical trials and ultimately targeted therapies for particular subsets of patients with DLBCL based on this molecular profiling.

So, my last report for the Leonard List or the number one Leonard List choice for ASH 2023 before we get to the bonus round is actually a split choice or a double choice, we'll call it 1A and 1B. 1A is Abstract 3761, entitled “Frontline Management Strategy and Quality of Life in Follicular Lymphoma: a Multi Institutional Prospective Cohort Study”. This is led by Dr. Tsang and colleagues from the Mayo Clinic and the LEO Consortium as well as the Mayo Clinic Iowa Molecular Epidemiology Resource, a great resource for data with patients with lymphoma. 

The second abstract 1B is from Koehler and colleagues, Abstract 498, entitled, “Longitudinal Analysis of Patient Reported Quality of Life in Newly Diagnosed Chronic Lymphocytic Leukemia, Stratified by Initial Management Strategy: A Multi Institutional Prospective Cohort Study”, and Kohler and colleagues are from primarily the Mayo Clinic, as well as a few other centers including Iowa. But this also, both of these abstracts utilize the Iowa Mayo SPORE Molecular Epidemiology resource, which has led to a number of different advances and bits of information in various lymphoma subtypes. 

So what's the theme here? Well, we have two subsets or two entities within the lymphoid, malignancy group. One is follicular lymphoma and one is chronic lymphocytic leukemia. We commonly observe these patients if they are asymptomatic and do not have indications for therapy. And the question that comes up for these patients really relates to what is the value with early treatment for these patients? We know that if you're asymptomatic and don't have indications for therapy, don't have bulky disease or other reasons to treat that observation is reasonable. 

We intuitively think that observation is a good thing for patients. They don't have to get therapy. But we know that that might be a double-edged sword with regard to quality of life. And the common theme of these is that there's an analysis looking at patient reported quality of life in patients with these indolent lymphomas and with a focus on patients who are observed. 

And in follicular lymphoma, the takeaway is that – this is by Tsang and colleagues, one of the largest studies looking at longitudinal quality of life for patients with follicular lymphoma –treatment has been associated with initially improvement in quality of life and then a lower degree of quality of life. 

However, interestingly, in the CLL study led by Koehler and colleagues, those patients who underwent initial observation actually had very similar quality of life over time compared to those who got initial therapy. 

So, I don't think that these are definitive studies by any stretch, because obviously physicians and patients chose to initiate therapy based on whatever factors led them to initiate therapy including patient and physician preferences and patient and physician discussions. One can envision that a patient who is told they should get therapy, or they need therapy might have a different feeling about that and the quality of life versus a patient who is not told or may hear about the uncertainties of the value of therapy. That might lead to a different quality of life or at least a different perspective on the disease.

But this really highlights the fact that we need to focus in follicular lymphoma and in CLL for watch and wait patients in particular, but in all patients, we need to have better tools to focus on quality of life because frankly for many patients who will not die of these diseases, but with these diseases, targeting quality of life and the choice of to treat or not to treat or what treatment to choose is really a key important factor in making this selection.

And I give these authors and researchers a lot of credit in trying to nail this down more. Unfortunately, it's not definitive to tell us what to do, but I do think we probably should be approaching it in a precision quality of life kind of format where it strikes me that some patients might benefit from intervention, and we should identify those patients and maybe treat them a little earlier to improve their quality of life or give them some strategies to cope with the disease. 

And others may benefit from a different approach. Whether it's intervention or observation, trying to figure out who manages better based on the nature or the choice of intervention or just doing an intervention or not is really important and valuable and something that I think we need to focus more and more of our efforts on as we look at patients and think about what is the best way to approach their disease when they have many options. 

So we're now going to pivot, and I'm just going to briefly give you our five bonus abstracts to keep an eye on. These are only going to be highlighted in the podcast, so thank you for listening here to the last part of the podcast. I’m not going to go into these on Twitter, but I think that they are of interest and worthy of your attention. And so little extra treat for those of you who decided to get into this topic and listen to the podcast. 

So bonus number one is actually a late breaking abstract led by Dr. Wang and colleagues from MD Anderson and elsewhere. It is Late Breaking Abstract 2, “Ibrutinib Combined with Venetoclax in Patients with Relapsed/Refractory Mantle Cell Lymphoma: Primary Analysis Results from the Randomized Phase 3 Sympatico Study”. 

This takes ibrutinib, which is a Bruton's tyrosine kinase inhibitor, and is been used in various settings in mantle cell lymphoma, including in the relapse setting for patients who have had one or more prior therapies. And it asks the question, what is the value of adding the BCL2 inhibitor venetoclax to ibrutinib?

So this is a randomized trial where patients were randomly assigned with relapsed mantle cell lymphoma to receive oral ibrutinib alone with placebo for two years or oral ibrutinib with oral venetoclax after a ramp up period also for two years followed by single agent ibrutinib until progressive disease or toxicity. 

So the patient stayed on the ibrutinib and received two years of the venetoclax versus placebo. And the net of this study is that the ibrutinib venetoclax combination had an improvement in progression free survival compared to ibrutinib placebo. Medians were 32 months versus 22 months, so an improvement by about 10 months in median progression free survival. The hazard ratio was 0.65 and there was a numerically, but not statistically, significant improvement in overall survival at this point in time. We'll be interested in further follow up there. 

Not surprisingly, there was a bit more toxicity with the addition of venetoclax neutropenia in particular, and other cytopenias, as well as diarrhea and COVID related complications, but to my eye, fairly similar overall, other than the cytopenia issues. Serious adverse events were occurred in about 60 percent of patients in each arm. So I think these are interesting findings because the duration of therapy is really not a huge issue here from the standpoint of you don't have one arm being on therapy of some sort or another in a differential amount of time. And the tolerability seems to be pretty manageable. 

We also don't use Venetoclax, as a single agent, so this is not a matter of early versus late Venetoclax, it's either Venetoclax versus no Venetoclax. And I think, again, a 10-month progression free survival difference significant hazard ratio with an oral therapy might make this approach one that is interesting and worthy of further consideration. That being said, ibrutinib is not used as much now in mantle cell lymphoma because we have other BTK inhibitors that are available, and so that throws a whole wrench into the application of this approach, but nonetheless I think this is interesting to consider how one will take it forward given that ibrutinib is used less often in favor of other BTK inhibitors now will be of significant interest. 

Next number two in the bonus round is Abstract 612 from Dr. Phillips and colleagues. Dr. Phillips is in Manchester, the UK. Most of the other authors of this study are from the UK. This is entitled “Bleomycin Affects Lung Function for at Least Five Years After Treatment for Hodgkin Lymphoma - Data from the International Randomized Phase III Rathl Trial”. 

The Rathl trial looked at patients with basically advanced stage Hodgkin lymphoma treated with ABVD initially, and then if they responded by interim PET scan, dropped the bleomycin in one arm or continued the bleomycin in another arm. And the primary analysis showed that you could drop the bleomycin in patients who had a PET negative at the interim time point. 

The results of this analysis are focused on bleomycin and lung abnormalities. And the takeaway here is that interestingly, a fair percentage of patients had abnormal pulmonary function tests as reflected by diffusion capacity at baseline and that bleomycin did not entirely predict bleomycin related changes in lung function. 

But interestingly, the changes in lung function, at least by the PFT assessments of diffusion capacity were long lasting and only partially reversible at five years. And so these data provide us with another reason to try to avoid bleomycin. And as we talked about earlier, more and more of our regimens and studies are moving away from the use of bleomycin.Next, number three in the bonus selection group is abstract 3128, “Neurocognitive Outcomes Over the First Three Months After CAR T Cell Therapy: Preliminary Findings from a Longitudinal Study”. This is from Dr. Mayo and colleagues. Dr. Mayo and colleagues are at the University of Toronto. 

And this is focused on looking at patients receiving CAR T cell therapy. We know that there can be neurocognitive effects of CAR T cell therapy, acutely as part of the immune response or ICANS and, cytokine release syndrome. This was a study that carefully looked at neurocognitive outcomes in 37 participants that were assessed at baseline at one month and then a smaller group at three months. 

And the net of this study is interesting, that about a quarter of patients had some neurocognitive impairment at baseline. This went up to 41 percent at one month and down to 17 percent at 3 months. And so, there's a lot of detail on these analyses that I won't go into. But the takeaway is that if you're looking at neurocognitive outcomes, be aware that patients at baseline may have some of these issues. They may fluctuate over time and I think like in other settings we do need to keep in mind neurocognitive issues in these patients and the potential impact of ICANs and CRS on neurocognitive long-term outcomes, but also I think just a close attention to this given the importance of neurocognitive functioning for patients is really important and something that is worthy of further study and analysis. 

Number four in our bonus group is from Dr. Moskowitz of Memorial Sloan Kettering and colleagues. And this is entitled “Ruxolitinib Promotes Clinical Responses in Large Granular Lymphocytic Leukemia Via Suppression of JAK/STAT Dependent Inflammatory Cascades”. This is a study of I think it's a subset of a larger phase two study that happen to include ruxolitinib is an inhibitor of JAK/STAT related pathways. There was a study of large granular lymphocyte leukemias, which are T or NK associated lymphoproliferative disorders, and a larger study of T cell lymphomas. There were a handful of patients with LGL leukemia included and some responses were seen. 

And so the author said, well, let's look at a larger group of patients. They expanded their phase two study to include 23 patients with relapsed and refractory LGL leukemia. And these patients have been through many of the standard therapies for LGL leukemia and the net is that there were 25 percent, or 5 patients, that had complete responses, 6 patients or 30 percent that had partial responses, and these were durable with 68 percent of patients being in remission at 14 months. 

And STAT3 mutational status predicted for outcome. Basically, if you had mutations, you were more likely to respond to ruxolitinib. We commonly treat these patients with cyclophosphamide or methotrexate, and it suggests that a high percentage of patients if they do have JAK/STAT mutations, that ruxolitinib may be a treatment choice that has some potential value. Small series, but a rare disorder, and I think very interesting findings to keep an eye on, and perhaps keep in mind for those occasional patients with recurrent disease and LGL leukemia.

Finally, the fifth choice for our bonus round is Abstract 67, “Comparing Clinical Characteristics and Outcomes of MYC and BCL6 Double Hit Lymphoma with Other Aggressive B-Cell Lymphomas: Understanding the Impact of the New WHO and International Consensus Classifications”. This is from Dr. Khurana from Mayo Clinic and a variety of other colleagues, mostly also at Mayo but also elsewhere. 

And this is an analysis of over 1,500 patients with aggressive lymphomas, aggressive B-cell lymphomas, and these investigators are analyzing the issue of double hit lymphoma which can have mutations or translocations of MYC and BCL6 double hit lymphomas also can include MYC and BCL2, as well as triple hit lymphomas where patients have all three. And so, the bottom line of this study is that the authors wanted to tease out are their differences of these MYC BCL6 double hit lymphomas from the other subtypes with regard to outcome. 

And the takeaway is that the double hit BCL6 group with MYC and BCL6 translocations are different than the DHL-BCL2 translocations. And in fact, have a better outcome. We have often lumped these two groups together in studies, but these suggest that the outcomes are different in the BCL6 group and potentially better in the BCL6 group. 

Again, is this a function of choice of therapy? It's not a randomized trial. It could be that they did better because they were treated more aggressively or treated in a different way, hard to say for sure, but bottom line is that these are not surprisingly biologically different diseases and ideally, we would be able to tease them out and approach them differently. 

I’m not sure we're going to be able to necessarily do that. In general, these patients were able to be treated more commonly with a higher intensity they tend to occur more in younger patients, so there are some confounders there but nonetheless this group of patients seem to do a bit better than the other subsets. 

And again, is it therapy related, is it biology related, is it a combination? It remains to be seen, but interesting data. And presumably, there'll be more to come looking at this subset of double hit lymphomas. 

So, hopefully I've given you a little bit of an overview of some of the things that I think are interesting and hot topics for ASH this year. 

I think we have new data in mantle cell lymphoma, new lymphoma subsetting data, some new agents out there, some new combination regimens and potentially standards of care, and also importantly highlighting quality of life and other factors that might influence treatment selection for certain subsets of lymphoma. 

So, I look forward to more details on these studies and more information being presented at the meeting and in the subsequent publications. I think some of these may affect future practice in some ways, but all of them, I think, raise important issues to keep in mind as we think about care for our patients and how we think about our research directions and approaches we can take, whether it's in the clinic or in the laboratory or in the outcome arena to potentially improve outcomes for more patients with lymphoma, and advance our field and our understanding of the biology of these diseases, as well as our approach to treating them in clinical care. 

So I want to thank you very much for joining me today and also invite you to download, subscribe, rate, and review Cancer Cast on Apple Podcasts, Google Podcasts, Spotify, or online at weillcornell.org. I also would like to encourage you to write to us at CancerCast at 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.