Transcription:
Leonard List 2021

Dr. John Leonard, MD (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 we will be discussing 15 of the most interesting lymphoma related abstracts to be presented at the 2021 Annual Meeting of the American Society of Hematology or ASH.

So the American Society of Hematology, for those of you who may not be familiar, is one of the largest organizations in the world focused on blood and blood cancer research and clinical care. And there is an annual meeting that is held where tens of thousands of people interested in blood and blood cancers gather and talk about the latest research, provide educational programs, have networking, and really work together to advance the field. And several years ago I set up something called the Leonard List. This is really just my thoughts about the most interesting and relevant abstracts relating to lymphoma. And this is the fourth year we've also done a review of the Leonard List on the podcast, CancerCast, which you're joining. And we have also added in addition to the 10 selections that I outline on Twitter. We add five bonus abstracts for those of you who have joined the podcast to get a little more detail. This is something that has taken off a little bit. I try not to pick necessarily the most noteworthy abstracts where everyone in the field is listening to or seeing the latest on – although I touch on some of those – I also try to pick a few things that I think are relevant to patients, relevant to research, relevant to the field, that perhaps go a little bit unnoticed.

And so this is just really my opportunity to give some thoughts on things that relate to the lymphoma field – research and of course, patients – and we're going to summarize them all here leading up to ASH in a little more detail than I can give on Twitter. So why don't we go ahead and countdown the 10 selections and then we'll get into the five bonus selections afterwards.

So the number 10 selection is actually, as I occasionally do, a 10a and a 10b. It's actually two selections. The reason being that they both have a similar theme. So the 10a selection is abstract 230 entitled "Ruxolitinib Plus Nivolumab in Patients with R/R Hodgkin Lymphoma after Failure of Check-Point Inhibitors: Preliminary Report on Safety and Efficacy." And the first author here is Dr. Bachanova and colleagues from the University of Minnesota in Minneapolis. In the number 10b slot is abstract 234 entitled, "Pembrolizumab Plus Vorinostat Induces Responses in Patients with Hodgkin Lymphoma Who Are Refractory to Prior PD-1 Blockade" and that's led by Dr. Alex Herrera from City of Hope in California.

So the theme here is really adding new drugs to an immune checkpoint inhibitor, in the first case, nivolumab and the second case pembrolizumab, in order to overcome a refractory state in patients largely who have disease that's refractory to the immune checkpoint inhibitors in Hodgkin lymphoma.

Immune checkpoint inhibitors essentially remove the shield that tumor cells may have that protect them from the immune system. And there are several of these available in different settings, but in Hodgkin lymphoma, we have nivolumab and pembrolizumab. And so, these are drugs that are approved in patients with recurrent Hodgkin lymphoma where they have somewhere in the range of about a 70 or 80% response rate. And in some cases can last much longer than a year in duration of response. So these are clearly valuable drugs for the treatment of patients with recurrent Hodgkin lymphoma.

Unfortunately, these don't work in some patients or they stop working in many patients. And so the idea of these two abstracts is to try to overcome this resistance or restore sensitivity.

So in the 10a choice, where ruxolitnib plus nivolumab was examined, this was a phase one/two multi-center trial adding to nivolumab the JAK2 tyrosine kinase inhibitor. And JAK2 induces PD-1 ligand expression, augments tumor cell proliferation, and JAK2 signaling can be inhibited by a number of different molecules, including ruxolitnib. And so the idea is that this study enrolled 19 patients. And they basically had advanced stage Hodgkin lymphoma, had had a number of previous treatments, and they were treated with the combination of nivolumab, which they had generally had before. All of the 19 patients had experienced progressive disease after immune checkpoint inhibition.

You would expect that very few of them would respond to a nivolumab again, given that they had disease that had progressed after it, and in the 16 patients evaluable for a response to the combination, the best overall response rate was 75%, including three complete responses or about 19% overall. And several of these patients went on to get other therapy. Others had fairly durable responses. And so this at least suggests that by inhibiting JAK2 signaling with ruxolitnib. You can essentially overcome resistance to an immune checkpoint inhibitor in this case, nivolumab.

Kind of a similar theme in the 10b Leonard List selection where pembrolizumab and vorinostat were combined. Again, this was a group of patients with advanced stage, recurrent Hodgkin lymphoma. And the concept here was that a histone deacetylase inhibitor could potentially restore sensitivity to PD-1 blockade. And so this was a phase one study looking at the efficacy and safety of pembrolizumab, a different checkpoint inhibitor, plus vorinostat, a histone deacetylase inhibitor or HDAC inhibitor in patients who largely had received prior anti PD-1 therapy.

And so this was really a study exploring this concept of overcoming checkpoint inhibitor resistance. It had 32 patients. They had a median of four prior therapies. The most common adverse events were hypertension, fatigue and some other, including GI side effects. In this study, 30 evaluable patients, the best overall response rate was 73%. The CR rate was 33%. And in patients who had disease refractory to prior PD-1 blockade, the overall response rate was 56%, CR rate 6%. And again, some of these responses were durable.

And so I chose these two together in our selection number 10 because the theme is really similar here. The idea that immune checkpoint inhibitors can work very well in Hodgkin lymphoma. Patients can develop resistant disease. But in fact, by adding, in this case, either a JAK2 inhibitor or a histone deacetylase inhibitor, there is at least some evidence that we can overcome the resistance to the checkpoint inhibitor, and in fact, restore sensitivity and induce a response. So I think this is very exciting.

There aren't a lot of settings in oncology and hematology where we have disease, a tumor that's resistant to one drug, but by adding a second drug, we restore sensitivity. It really leads to a number of different potential future studies where perhaps one might look at these combinations after immune checkpoint inhibitors or one might compare an immune checkpoint inhibitor as a single agent to a combination of an immune checkpoint inhibitor with one of these sensitizing agents.

So I think these are interesting data worthy of future study. And certainly by the efficacy that was seen, one might argue that these might have a clinical place in the future, particularly in Hodgkin lymphoma patients that have been through a number of different regimens, might have limited options. To be able to restore sensitivity to a drug that works as third- or fourth-line therapy in some cases may be quite helpful.

And the other thing that I think is of note here is that immune checkpoint inhibitors are used in lots of different settings in oncology. And it makes you wonder, could these principles, and could these approaches be employed in other tumors as well? So more to come there. I think an interesting paradigm that we'll probably see more of in the future.

We'll now move to number nine selection of the Leonard List for ASH 2021. And this is little bit different type of selection, abstract 566, "Enrollment of Black Americans in Pivotal Clinical Trials Supporting Food and Drug Administration (FDA) Chimeric Antigen Receptor (CAR)-T Cell Therapy Approval in Hematological Malignancies."

So CAR T cells are an important therapy for many forms of blood cancer, particularly certain lymphomas, B-cell lymphomas as well as, acute lymphocytic leukemia and now multiple myeloma. And they've really become a mainstay of therapy, particularly for patients in certain settings where a number of other prior treatments haven't worked.

There are problems with enrollment in clinical trials, a minority of patients are enrolled in clinical trials across the country, across the world. And when you start to look at different populations, you see that there are significant disparities. Black Americans, in particular, are underrepresented in clinical trials in a number of different settings. And so this was a retrospective analysis. The first author here is Dr. Samer Al Hadidi from the Winthrop Rockefeller Cancer Institute in Arkansas.

And this was a retrospective analysis of seven pivotal trials looking at the approval studies for CAR T cells for hematologic malignancies, so really all of the key pivotal trials. And what the authors did, they looked at the data from these various enrolled patients. There were 782 patients out of the 1051 patients that were enrolled where efficacy was reported. And the net was that black individuals constituted only 28 patients from these trials, or 3.6%. Most of these patients had either diffuse large B-cell lymphoma or multiple myeloma. Two of the seven studies didn't report ethnicity or race and/or included black individuals under the "others" ethnic category. And so the net of this was that basically enrollment as reported in these trials, number one, potentially wasn't optimally reported. There was limited data.

And I think most importantly, black individuals were underrepresented in clinical trials that supported CAR T-cell therapies for various hematologic malignancies. This is particularly profound and relevant in multiple myeloma, where there is an increase prevalence of multiple myeloma among black individuals. Yet, black individuals were underrepresented in the clinical trials leading to CAR T cell approvals in myeloma. And so this highlights that the conclusions of the authors – and I would wholeheartedly agree – that efforts should be made to enroll more black individuals in clinical trials that include novel, potentially beneficial CAR T-cell products.

And this is important in making access available to a broad population of individuals that can potentially benefit, as well as gathering data from representative populations and representative sub-groups of patients who have these malignancies. And so again, I just wanted to highlight the importance of efforts to really recruit patients to clinical trials in general, and in particular, to make sure that we are doing what we can to expand the representation of individuals enrolled to clinical trials from different backgrounds.

Now we'll move to number eight on the 2021 ASH Leonard List. And this is abstract 709 entitled "Tumor-Confirmed Follicular Lymphoma Mutations Are Detectable in Peripheral Blood Years Prior to Clinical Diagnosis." And the first author is Dr. Schroers-Martin and colleagues primarily from Stanford as well as several other groups.

And so this is looking at the idea that can we potentially detect evidence of follicular lymphoma – which is the most common indolent lymphoma and second most common lymphoma overall – can we detect evidence of follicular lymphoma well in advance of a clinical diagnosis? I think this is really important and potentially provocative.

So what the authors did was look at evidence of chromatin modifying genes, including KMT2D, CREBBP, EZH2, and EP300. These are early events it is felt in follicular lymphoma. And so the idea of being here, could one detect evidence of these mutations well in advance the diagnosis?

And so this study accessed the American Cancer Society Cancer Prevention Study LifeLink cohort which had collected screening blood and saliva samples from over 100,000 cancer-free American participants between 1998 and 2002. So essentially, individuals felt to be without cancer, and looked at detection of tumor confirmed variants and pre-diagnostic specimens.

So they identified 29 follicular lymphoma patients with biopsies ultimately in this population and looked at their screening and looked at blood – I should say that was taken before their diagnosis – and looking the tumor biopsies for commonly mutated lymphoma genes. And I won't get into the details of the technical aspects of this, but the net is that there were coding mutations identified in the tumors and that the researchers could identify tumor derived variants in seven of 29 paired pre-diagnostic specimens – so about a quarter of the specimens – at a median of 44 months, as long as 112 months prior to diagnosis.

And so this raises the idea that you can identify these mutations in peripheral blood and saliva years prior to a clinical diagnosis with a spectrum of variants that are enriched in follicular lymphoma-associated mutations. And the question is, could this potentially stratify individuals that are at risk for malignancy? This sort of analysis or study is one that is being used in a number of different cancer screening tests that are either coming onto the market or coming into some clinical evaluation.

And again, it raises the idea that we don't tend to think about diagnosing follicular lymphoma particularly early. Often we watch and wait patients that have a clinical diagnosis. But it raises the idea that, could one at least consider if you were to identify these early mutations in early evidence of disease, is there some sort of preemptive strategy that one might envision? It would be a long way before we would show that that is something that is either feasible or beneficial, but I think it's an interesting concept that warrants further evaluation.

Now moving to abstract number seven on the 2021 ASH Leonard List. Here we go with abstract number 654 entitled "Early signals of anti-tumor efficacy and safety with autologous CD5 CAR T cells and patients with refractory or relapsed T-cell lymphoma" by Dr. Rouce and colleagues at Baylor College of Medicine.

So this is an interesting approach. We know that CAR T cells, as we alluded to earlier, are used to target B cell antigens, particularly CD19 in B-cell lymphomas. This is an early study using a CD5 targeted chimeric antigen receptor or CAR to go after T-cell lymphomas.

T-cell lymphomas are about 10% of lymphomas. They tend to be more challenging to treat. They have a number of different treatment options, but many patients have recurrent or refractory disease, so new approaches are needed. And this was a CAR T-cell construct that targets CD5. CD5 is something present on T-cell lymphomas, as well as typically normal T cells or many normal T cells.

And so this was an early phase study. It looked at a relatively small number of patients. But the net is that four out of nine patients, or 44%, achieved responses in this dose-escalation study. This enabled three of the patients to go on to allogeneic stem cell transplantation. There were a couple of complete responses here.

And so this is just another example of CAR T cells being explored. However, in this case, not against the B cell target antigen. But a T-cell target antigen with early evidence of safety and efficacy, obviously much more work to do here. But an interesting approach and something I'm sure we'll hear more about.

Moving now to number six in the Leonard List 2021 for ASH is abstract 304 entitled "Efficacy of Ibrutinib, Rituximab and Mini-CHOP in Very Elderly Patients with Newly Diagnosed Diffuse Large B Cell Lymphoma: Primary Analysis of the Australasian Leukaemia & Lymphoma Group NHL29 Study" and this is led by Dr. Verner and colleagues.

The idea here is that many older patients and patients who are frail with diffuse large B-cell lymphoma are treated with a mini or lower dose version of R-CHOP, which is the standard therapy for most patients with diffuse large B-cell lymphoma. R-mini-CHOP is effective in roughly half of patients that fall under this category.

There's been a lot of interest in this population of patients in part, because they tend to have less favorable lymphomas, harder to treat lymphomas also because they tend to be less able to tolerate therapy given their age and comorbid illnesses. And so the idea of building upon R-mini-CHOP by adding additional drugs is certainly something that is of interest.

And so this was a prospective multicenter phase two study of patients over the age of 75, treated with R-mini-CHOP in combination with ibrutinib. Ibrutinib is a Bruton's tyrosine kinase inhibitor; it's been used in a randomized trial with R-CHOP. There was some evidence in the younger patient subset that it could provide some benefit in the nongerminal center subtype of diffused large B-cell lymphoma. However older patients had more toxicity and the trial was negative.

But this trial giving lower doses of the mini "R" in the mini-R-CHOP regimen added Ibrutinib again, to see if there could be potential benefit. And I think this is a new paradigm.

There's a U.S. intergroup study looking at oral azacitidine in combination with R-mini-CHOP, that's stemmed from, the research of my colleague Leandro Cerchietti at Weill Cornell. So again, adding to R-mini-CHOP as an interesting strategy. So in this trial the median age was 82. And so the patients were older. They tended to have advanced stage disease and higher risk disease.

And in this population of patients, the two-year overall survival was 68%. This was similar to the null hypothesis, not significantly different. The median overall survival was not reached and essentially the toxicity data suggested that for most patients, that this combination was deliverable. And not a randomized trial, but suggested that the two year progression-free survival look good relative to what has been reported to R-mini-CHOP alone.

And so an interesting set of data in older patients suggesting that this is a population of patients where new approaches are needed, the addition of new agents to R-mini-CHOP make sense. One has to be careful about the toxicity, particularly in older patient population, but it is also a nice place to study new drugs, because you can make an impact or potentially see an impact when you add a new drug to R-mini-CHOP in a way that might be harder to detect when you do it in a more favorable or broader patient population.

Next moving to abstract five in the Leonard List, ASH 2021. This is abstract 51 entitled "Mental Health Among Patients with Non-Hodgkin Lymphoma: A Danish Nationwide Study of Psychotropic Drug Use in 7,201 Patients and 36,005 Matched Comparators." This was led by Dr Øvlisen and colleagues from Aalborg, Denmark.

So I picked this because this is really an issue that is of great importance to patients with cancer. And we and others have seen this as a potential issue for patients with lymphoma. The idea that a cancer diagnosis is associated with psychological distress, this can be associated with or lead to mental health problems. You can envision that being ill, dealing with a cancer diagnosis and other factors could contribute to the need for mental health support and care for patients. With lymphoma, other cancers and obviously other significant illnesses.

So this was a very large study trying to get some insights into the psychological distress associated with non-Hodgkin lymphoma. It was a population-based nationwide cohort study, looking at prospectively collected data from Danish registries, and basically it analyzed over 7,000 patients with lymphoma and 36,000 matched comparators. About 40% of patients had follicular lymphoma and another 40% had diffuse large B-cell lymphoma.

And it turns out that when you look at psychotropic drugs – which are basically antidepressants, anxiolytics, and anti-psychotics – the use of psychotropic drugs was higher in patients with lymphoma, at about 16% compared to the match comparators that were at 5.7%. And this was higher in patients with aggressive lymphoma. And this was also higher or this association and risk was greater in the first years following diagnosis. So it really suggests, and I think calls attention to the important fact that patients with lymphoma have a significantly higher risk in this cohort of mental health problems compared to the Danish background population when using the prescriptions for psychiatric medications as a proxy here.

And so, there are some confounders here. There are some proxies being used here, but it highlights the fact that, at least by this one measure, that higher rates or significant rates of psychiatric issues, were detected in patients with lymphoma. And I think this highlights the fact that practitioners and patients need to be aware of this potential issue. You can certainly envision that patients with lymphoma and other cancers and serious illness may have increased need for psychiatric support and mental health support for obvious reasons. But I think those of us that are dealing with patients with lymphoma, or those who may be patients with lymphoma, should be aware of this, the potential need for help and services for patients with lymphoma. And if you're a patient with lymphoma dealing with mental health issues, it also says that you're not alone and you should really be exploring this and getting the help that you need.

I want to now move to Leonard List abstract number four from ASH 2021. This is abstract 815, "Long Term Follow up of the Resort Study (E4402): A Randomized Phase III Study Comparing Two Different Rituximab Dosing Strategies for Low Tumor Burden Follicular Lymphoma." This was led by Brad Kahl and the ECOG, the Eastern Cooperative Oncology Group, Lymphoma Committee.

So this was an important study. E4402 was a randomized phase three study comparing two different rituximab dosing regimens for patients with previously untreated low tumor burden follicular lymphoma. And so this was a group of patients with low tumor burden, follicular lymphoma, receiving four doses of rituximab as initial therapy. Then the responders were randomized to maintenance rituximab, one dose every three months, or retreatment rituximab, weekly for four doses at the time of disease progression.

And the primary end point was basically time to treatment failure. Really a focus on duration of rituximab benefit. This trial, I think, has led many people to – including myself – question the value of rituximab maintenance, because what it showed was that the duration of rituximab benefit was quite similar whether you stayed on rituximab maintenance or retreated in this situation with rituximab at the time of progression.

So this was a long-term follow-up analysis of this group of patients who had a median follow up of 8.7 years. And interestingly, at seven years, 83% of the maintenance rituximab, and 63% of the rituximab retreatment patients remain free from their first cytotoxic therapy. And so the majority of patients at seven years in this group did not require cytotoxic therapy. Essentially, the mileage that they got out of single agent rituximab was quite substantial and the majority of patients had not needed any other therapy at seven years of follow up. There was no difference in overall survival. It was similar, which approach was there, and really no significant difference in histologic transformation.

And so, I think that this really highlights the fact that single agent rituximab for low tumor burden patients with follicular lymphoma can be quite an effective therapy, can give a subset of patients – in this report, the majority of patients – a substantial duration of going with single agent rituximab and not needing chemotherapy over several years. I think it also validates this approach for patients who do choose the strategy to manage their low tumor burden follicular lymphoma.

Now we'll move to abstract three in the 2021 ASH Leonard List. This is abstract 661, entitled "Financial Hardship Amongst Patients with Hematologic Malignancies: Using the EMR to Streamline and Prioritize Patient-Centered Care." This is by Dr. Voleti and colleagues at the Mayo Clinic. They looked at a cohort of over 10,000 patients treated at any of the Mayo Clinic Cancer Centers across the country. This is in 2018 to 2020. They looked at patients with lymphoma, leukemia, plasma cell disorders, myelodysplastic or myeloproliferative disorders and other hematologic malignancies.

And the bottom line of this study was that there was a fairly straightforward way, as part of the screening for issues of financial hardship, there was a single question asked of patients. And the question was, how hard is it for you to pay for the very basics like food, housing, medical care, and heating? This was asked of patients on a five-point scale, including "not hard at all" ranging from there to "very hard." And the analysis in this group for patients was really to look at the prevalence and predictors for financial hardship using this metric. And so they extracted this data from the electronic medical record.

And the net of this analysis was that financial hardship was reported by about 12% of the patients overall. And a higher rate in Hispanic versus non-Hispanics, Black and American Indian, Alaska native groups versus whites. Other factors were associated with significantly less likelihood of financial hardship, including insurance status, diagnosis, age, distance from the cancer center.

And so I found this interesting because we know that financial hardship is an important issue for patients in dealing with the cost of their care, accessing care, accessing their medications. This was one group of centers, and it may vary at different centers across the country, but it highlights the fact that asking a simple question – which can be to some degree automated, perhaps through the electronic medical record – gives a significant amount of information.

I'm going to add on a selection, 3b to this group, and this is abstract 567, "Worsening Financial Toxicity Among Patients Receiving Chimeric Antigen Receptor t-Cell (CAR-T) Therapy: A Mixed Methods Longitudinal Study." And this is by Dr. Cusatis and colleagues at the Medical College of Wisconsin. A similar theme looking at adult patients receiving CAR T-cell therapy. And this looked at 28 patients where they looked at questionnaires, looking at issues around financial impact of CAR T-cell therapy.And this study highlighted the fact that a substantial fraction of patients receiving CAR T-cell therapy also had challenges of financial import as well.

I batch these two to highlight the issue of financial toxicity, financial hardship for patients with lymphoma, and no doubt, other cancers, and again, an important parameter that we need to follow as caregivers and really address this as part of the support we provide the patients with lymphoma and blood cancers. And if patients aren't able to manage their care, get their medications, or come for treatment, that's going to impact their outcomes, as well as the daily challenges that they face.

Now we'll move to number two in the 2021 ASH Leonard List. This is abstract 130 entitled "Glofitamab Step-up Dosing Induces High Response Rates in Patients (pts) with Relapsed or Refractory (R/R) Mantle Cell Lymphoma (MCL), Most of Whom Had Failed Prior Bruton's Tyrosine Kinase Inhibitor (BTKi) Therapy," I'm going to say that the therapy failed the patients, but in any event, this is an interesting study led by Dr. Tycel Phillips and colleagues. Dr. Phillips is at University of Michigan.

So Glofitamab is one of a family of bi-specific antibodies. There are a number of them out there. And this has a two-to-one configuration with biovalency for CD20 on B cells and monovalency for CD3 on T cells. So it's engaging the tumor on the CD20 using CD20 on the B cells and CD3 on the T cells to engage the T cell in proximity of the tumor. There are some reasons why this has been combined with obinutuzumab, a CD20 antibody, to modify the receptor occupancy of glofitamab and potentially affect its clearance and potentially the risk of cytokine release syndrome.

So the net of this study was that 29 patients had received glofitamab in combination with obinutuzimab in this trial. This was a group of patients with mantle cell lymphoma who had median age of 69, had advanced stage disease. Sixty-nine percent of the patients, so the majority, had prior Bruton's tyrosine kinase inhibitor therapy, a number also had prior lenalidomide. Then, about half the patients were refractory to their first-line therapy or their prior therapy.

So in looking at the overall response rate, 81% of patients had a response. The complete metabolic rate was 66%, so a very high response rate. In patients who had prior BTK inhibitor therapy, the overall response rate was 82% and the complete metabolic response rate was 64%. So this is a pretty high efficacy, I would say, in patients who had disease that was resistant to BTK inhibitor treatment.

BTK inhibitors are really an essential part of the treatment for patients with mantle cell lymphoma, typically as a second line therapy, perhaps later. Now there are regimens looking at it as first-line therapy for patients who have disease resistant to a BTK inhibitor. We're often moving toward CAR T cell therapy, but if glofitamab is a therapy that is effective, has a high response rate, and if these turn out to be durable, it may be that this is an approach that has applicability and potential benefit for a substantial number of patients. So it'll be interesting to see where glofitamab goes forward in patients with recurrent mantle cell lymphoma.

Finally, in our group of Leonard List ASH 2021 abstracts. The number one choice is abstract 655 entitled "Clinical Significance of Clonal Hematopoiesis in the Setting of Autologous Stem Cell Transplantation for Lymphoma." This is led by Dr. Barouch and colleagues from a multi-center group, largely from Toronto, Canada.

So CHIP, or clonal hematopoiesis of indeterminate potential, is really recognized as a very important factor in various disorders. In fact, one of the plenary talks at ASH this year is focused on neurologic toxicities or neurologic risks and clonal hematopoiesis. We have identified clonal hematopoiesis as a risk factor for a number of diseases, a prognostic factor for a number of different cancers and cardiovascular disease.

We have been screening more and more patients in the setting of autologous stem cell transplant for clonal hematopoiesis, the concept being that these patients often have had a number of prior chemotherapies, they may be at risk for secondary malignancies. And so the question comes up well, when we see clonal hematopoiesis, what is the impact of this in a patient getting autologous stem cell transplant? Is this something that we should be concerned about? Is this something that says the patient is at greater risk for a secondary malignancy? What is the clinical significance of this?

And so this study looked at 420 residual apheresis products from patients who had undergone autologous stem cell transplant for lymphoma at Princess Margaret Hospital and looked for clonal hematopoiesis looking for 36 genes relating to myeloid neoplasm mutations. And basically all of these patients had recurrent lymphoma except for a subset of patients who had mantle cell lymphoma as part of their upfront therapy received a transplant.

So in looking at this issue what was found is that evidence of clonal hematopoiesis was seen in 181 out of 420 patients, or about 43%. And in 64 out of the 181 patients there was more than one mutation identified. And so this is pretty high. The idea that a substantial fraction of patients have evidence of clonal hematopoiesis is noteworthy the most frequently mutated genes were PPM1D, TET2, DNMT3A and several others.

And it turns out that when you look at these patients, you might want to know how did this affect or correlate with outcome. Patients with clonal hematopoiesis had inferior five-year overall survival from the time of first relapse, 38.9% versus 45.5%. So not a huge magnitude of difference, but statistically significant. However, it did not appear to have an impact on the risk of post-transplant relapse. And in fact, there was not an increase in secondary malignancies, secondary myeloid neoplasms, in the patients that had clonal hematopoiesis, at about 3% in each group. And so the net is, the clonal hematopoiesis was associated with delayed neutrophil and platelet engraftment and increased risk of death after autotransplant, but no difference in secondary myeloid neoplasms.

And so I think we'll continue to learn more and more about clonal hematopoiesis, but this is an interesting study with potential implications, both positive and negative from the standpoint of patients getting an auto transplant. To me, it argues that while we will be more concerned about patients who need an autotransplant and have clonal hematopoiesis, it does not appear that that transplant is contraindicated based on the fact that these patients can still do well, but more data to come.

So now we enter our last few minutes and we're going to go into just five bonus abstracts to share with you based on the fact that you've joined our CancerCast podcast today, to give you just a few extra thoughts. These didn't quite make the cut as being the highest impact, but still I thought warranted a little bit of attention. So I'm going to give you a couple of minutes on these before we wrap up.

Abstract 39, entitled "An EZH2 Gene Expression Signature Is Predictive of Differential Efficacy of Chemotherapy Irrespective of EZH2 Mutation Status in Patients with Follicular Lymphoma Treated within the Gallium Trial."

GALLIUM trial was a study for initial therapy of follicular lymphoma, treating patients with a chemotherapy backbone of either CHOP, CVP or bendamustine in combination with either rituximab or obinutuzumab as initial therapy. And the primary analysis of this study showed what I would say modest benefit of obinutuzimab in progression-free survival. No difference in overall survival.

The hypothesis in this study was that EZH2 mutations or an EZH2 gene expression signature, which is largely, but not entirely, attributable to EZH2 mutations, might correlate with outcomes with the chemotherapy. We've seen some of these data before, but the net is that these data suggest that the presence of either an EZH2 mutation or an EZH2 gene expression signature identified in this study, seem to basically correlate with a differential efficacy of chemotherapy backbones in combination with either rituximab or obinutuzumab.

So the idea is that patients without the EZH2 mutation or grouped into the cluster had longer PFS with CHOP or CVP-based therapy, whereas patients grouped into the EZH2 wild-type cluster had a longer PFS with bendamustine based regimens.

And so the idea that you could have either a mutation or a gene expression profile, perhaps associated with a mutation that could provide a differential benefit or efficacy of chemotherapy is interesting from the standpoint of potentially leading one to choose one chemotherapy over another.

And so these are early. They're a retrospective analysis, but certainly hypothesis generating, that we might be able to use this information to choose chemotherapy better, which as of now, we really don't have a good predictor or factor to choose which chemotherapy is better for patient beyond the presence or absence of transformation and patient and physician preferences.

I'll move to abstract 456, "A Randomized Placebo-Controlled Trial of Primary Prophylaxis with Weekly Alendronate Against Glucocorticoid-Induced Osteoporosis in Lymphoma Patients Treated with Steroid-Containing Chemotherapy." This is from Jensen and colleagues in Aalborg, Denmark.

We've seen more and more data out there now suggesting that patients with lymphoma who, particularly, are treated with glucocorticoids, are at risk of osteoporosis and potentially an increased risk of bone fractures. So this is an important long-term survivorship issue for patients with lymphoma. And we really have not done a whole lot, I would say, as a community in looking for this routinely. I think other abstracts and past years of ASH and publications have suggested that we should be looking at bone density in patients with lymphoma, particularly those who've been treated with glucocorticoids.

This was a single center, randomized double-blinded phase two study where patients with lymphoma who received a glucocorticoid containing chemotherapy regimen, such as R–CVP or R–CHOP were randomized to weekly oral alendronate or placebo for a year. And the primary end points, including their lymphoma outcomes, were really focused on assessments of bone mineral density and vertebral fracture risk at 12 months. The main end point, however, was lumbar spine T-score and changes from baseline to 12 months.

And the net of this study was that alendronate was a safe and effective primary prophylaxis in this group of patients. There were improvements in a number of different biomarkers of bone resorption and bone formation, and essentially suggests that this could be an important strategy for patients receiving glucocorticoids as part of their lymphoma therapy to potentially reduce their risk of bony disease, bony fractures. A longer and bigger study would be needed to look at the clinical end points, but some of the biomarkers and surrogates suggested the potential benefit of this approach. And one that highlights the fact that we need to be paying attention to bone health, and potentially as a research community to look at interventions as a prophylactic strategy.

Now we'll move to abstract 302, "Allogeneic CAR-T PBCAR0191 with Intensified Lymphodepletion Is Highly Active in Patients with Relapsed/Refractory B-Cell Malignancies." This is led by Dr. Bijal Shah from Moffitt Cancer Center. The senior author was Dr. Koen van Besien of Weill Cornell, a colleague of mine. And we've had patients treated on this trial as well.

The idea of this is, rather than autologous CAR T-cell therapy, this is using allogeneic CAR T-cell therapy, a CD19 directed cellular therapy using essentially a universal donor as opposed to the patient. And the idea being that this may be a potential off the shelf strategy. These patients receive lymphodepleting chemotherapy. There were 21 patients treated, 16 of whom had non-Hodgkin lymphoma, five of whom had B-cell ALL. They were heavily pretreated, a median of seven lines of therapy. A number of them had previously received a CD19 autologous CAR T-cell construct.

And so the net of this study was that overall, 15 of the 18 patients responded, or 83% of those who were evaluable, similar rates in both NHL and ALL. Complete responses were seen in almost two thirds of subjects. And a number of them are ongoing at six months or longer. And so this suggests that an allogeneic CAR T-cell construct can be potentially effective and safe as a anti B-cell malignancy therapy and something that I think we'll be watching more of – whether or not that comes instead of the standard CAR T-cells or after the standard CAR T-cells remains to be seen.

Next we'll move to abstract 381, "Pirtobrutinib, A Next Generation, Highly Selective, Non-Covalent BTK Inhibitor in Previously Treated Mantle Cell Lymphoma: Updated Results from the Phase 1/2 BRUIN Study." This is led by Dr. Wang and colleagues. The idea here is that while covalent BTK inhibitors have been widely used in B-cell malignancies, including mantle cell, the issues around the covalent BTK inhibitors can affect bioavailability, half-life and other factors. And so the idea of a non-covalent BTK inhibitor that is selective can potentially overcome resistance and be useful in certain settings.

This was a large study. The Bruin study has been reported before, 323 patients about half of whom had CLL/SLL about 61 of them had mantle cell. A variety of other malignancies were seen as well. And focusing on the mantle cell group of patients, there were 61, median of three prior regimens. Almost all of them, 93%, had received a prior BTK inhibitor. And the net is that the overall response rate was 52%, including 25% CRs. And the median follow-up was relatively short at six months, but it really suggests that a non-covalent BTK inhibitor can be effective and well-tolerated in patients where a covalent BTK inhibitor is no longer working or no longer tolerated. And so I think this suggests the potential future role for pirtobrutinib, and it's moving along in a variety of different clinical trials. It'll be interesting to see where the dust settles with this agent in the future.

And then finally I'll highlight one last bonus abstract. This is abstract 886, "Prognostic Value of Early PET in Patients with Aggressive Non-Hodgkin Lymphoma Treated with Anti-CD19 CAR T-Cell Therapy" led by Dr. Crombie and colleagues. This was a multi-center, retrospective study of patients with lymphoma who received commercial anti-CD19 CAR T-cell therapy, all of whom on this analysis had received a PET scan roughly 30 days after their CAR T-cell infusion. It included 193 patients overall.

And the question is, how did the PET scan correlate with subsequent outcomes? So when you look at the entire cohort, it was fairly typical for CAR T-cell populations with a fair number of prior therapies, median PFS of about 11 months. And the question here was really, did the day 30 PET scan correlate with outcome? And the net is that the PFS, as you would expect, was improved in patients who are in a CR at day 30 PET, and that the Deauville one or two patients looking at the PET assessment scale seemed to have similar outcomes as those with Deauville three.

So it suggests that if the patient is in a Deauville one, two or three at 30 days after their CAR T-cell therapy for lymphoma, their outcomes are relatively favorable. Whereas if they are not, they are less favorable. And this identifies a population of patients that requires potentially further intervention because their prognosis and subsequent outcome is going to be less good.

This is actually a population of patients that will be soon studied in the U.S. Intergroup that is looking at this group of patients at adding a number of different interventions in a randomized phase two fashion, to see if you can take that population of patients and improve their outcome once you identify them as being high risk for relapse by giving them additional therapy. And so this is a study that's coming along and I think validates this analysis, validates the importance of PET at day 30 in predicting outcome for patients treated with CAR T-cell therapy.

So this has been a great summary, kind of a whirlwind. I hope it was helpful to you. I think that ASH is really a great meeting for lymphoma, for blood cancers and blood diseases in general, both in research and in clinical care. We've talked about, and we'll see more data presented on clinical trials with new drugs, lymphoma and blood cancer biology. There'll be more data, certainly on CAR T-cells and other new agents. We'll see more data with circulating tumor DNA, and several abstracts, some of which we've highlighted, looking at aspects of disparities and financial toxicity, which are important to patients as well as mental health and other survivorship issues.

So there's really lot going on in lymphoma and blood cancer research, a lot of different areas that touch patients, that touch research and clinical care. And, hopefully, I think these are insights that will lead to changes and improvements in clinical practice and move the field forward and ultimately help to improve outcomes for our patients.

So thank you for joining us today for this overview. If you want to give some feedback and discussion around these abstracts, we'll be counting them down day-by-day in the 10 days leading up to ASH. If past experience is a guide, there will be lots of comments and input on Twitter. So I encourage you to tune into that. See what other people have to say about these abstracts and their thoughts. And some will agree. Some will disagree. That's the beauty of the whole exercise. And I look forward to these interactions and discussions.

I also invite you to download, subscribe, rate, and review CancerCast on Apple Podcasts, Google 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.

And I'll highlight that we have lots of past topics covering the waterfront of areas of cancer and cancer care and research. And we have lots of new podcast episodes in the pipeline coming forward. So please tune in and, keep an eye out for things that are of interest to you.

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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