Transcription:
Leonard List 2019

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 for today’s episode, we will be reviewing the 2019 Leonard list for the American Society of Hematology Annual Meeting. The American Society of Hematology or ASH is the world’s largest professional society that serves clinicians and scientists who work to cure, manage and understand blood diseases including blood cancers. For just over 60 years, ASH has hosted an annual gathering of hematologists from across the world to discuss and debate the latest research and discoveries in the field. This is really a meeting where the leading areas of hematologic blood cancers and other blood disorders are discussed in detail and it’s full of new information, new studies that are presented either in poster form or in oral presentations or published.

And there are thousands of what are termed abstracts that are presented at the meeting one way or another. So, a few years ago, I started what I termed the Leonard list on Twitter as a way to highlight research that I find particularly interesting or impactful in relation to lymphoma or sometimes other blood cancers. So, my strategy with this has been to post one abstract per day on Twitter in the ten days leading up to the ASH annual meeting. And this list has often sparked further dialog online amongst colleagues, amongst patients and others in the field.

And my goal here is not necessarily to present the top abstracts or the abstracts that are at the plenary session but really to highlight things that I think perhaps have a little bit special bent or may otherwise go unnoticed as well as abstracts that I think will potentially change the field as we approach research and as we approach clinical care for lymphoma patients.

Last year in addition to the Twitter countdown, we added on the CancerCast podcast an oral review of my top ten abstracts and we added in five bonus abstracts. And so you found this which is great and hopefully you’ll find this information new and interesting and perhaps complimentary if you follow it in Twitter and of course the five bonus abstracts are only for those of you listening as opposed to just seeing it on Twitter. So, hopefully you’ll see some added value there.

And I would highlight that this is really something that should be interactive and if you are following on Twitter or otherwise and want to give me feedback on this or your thoughts on this as you hear what I think, I’m happy to receive it. Also, just to reference the abstracts covered today, you can head to my Twitter which is @JohnPLeonardMD. Over the course of the ten days before ASH which is coming up now in late November depending on when you are hearing this. And all of the Tweets for each day have a link to the abstract itself so you can take a look directly at the data.

So, why don’t we go ahead and get started. So, with our first kind of top ten countdown, we’ll start off with Abstract 352. This is entitled Subcutaneous Rituximab Mini CHOP versus Subcutaneous Rituximab Mini CHOP Plus lenalidomide or R2 Mini CHOP in Diffuse Large Cell Lymphoma. For patients of 80 years or more, called the Senior Study, multicentric randomized phase III trial of the LISA which is the French cooperative lymphoma group.

So this is a fairly straightforward randomized phase III trial that focused on patients over the age of 80 with newly diagnosed diffuse large B cell lymphoma and it asked the question does lenalidomide improve the outcome of mini CHOP treated patients. The addition of lenalidomide improved the outcome of mini CHOP treated patients. CHOP is one of the standard chemotherapy regimens for diffuse large B cell lymphoma, RCHOP is the addition of rituximab to it and for older patients, particularly in the range of 80 or more; a reduced dose or Mini dose of CHOP is given and has been associated with good long term outcomes. And has more or less become the standard treatment based on a phase II trial.

So, lenalidomide which is an immunomodulatory drug has been studied in combination with various treatments in lymphoma and there have been studies combining it with CHOP that have had debatable results or different results I should say. The net is that it does not definitively improve the outcome of patients treated with the standard CHOP or RCHOP chemotherapy. And in fact, this study also showed really no difference between the two arms. Patients treated with R mini CHOP in the over age 80 group, 80 or older versus patients treated with lenalidomide plus R mini CHOP had similar efficacy outcomes.

So, that’s kind of the bottom line of the study. And I think this is important and why I chose this study was partly for that. It’s more information on how much lenalidomide does or does not add to an R chemotherapy containing regimen. But it also is really the first prospective phase 3 trial in this patient population that is 80 years or older with patients with newly diagnosed diffuse large B cell lymphoma. This had about 150 patients in it and I think this is a very impressive accomplishment by these investigators and also highlights the need for these patients to enroll in clinical trials and I’ll highlight that the US Inter Group led by the Southwest Oncology Group will be conducting a similar trial using azacytidine in the near future rather than lenalidomide.

And so, I think this is again, an important patient population that we should try to include in patient trials that is the elderly over the age of 80 with diffuse large B cell lymphoma. And I think it’s also an opportunity to test new drugs with a chemotherapy – chemoimmunotherapy regimen going forward.

The next study is Abstract 124 entitled Early Stage Follicular Lymphoma First Results of the FIL MIRO Study, a multicenter phase II trial combining local radiotherapy and MRD driven immunotherapy. And I think this is an innovative prospective trial that tackles the scenario of newly diagnosed patients with limited stage, stage one or two follicular lymphoma. There have been data generated over many years suggesting that somewhere in the range of 40% of patients treated with radiation depending on a number of different factors with limited stage follicular lymphoma can have good long term outcomes with remissions lasting ten to fifteen years or longer.

That has raised the concept that perhaps these patients may be cured and therefore many patients with limited stage follicular lymphoma are treated with radiation therapy with what we would term curative intent. But this concept of cure in follicular lymphoma is quite complicated because unfortunately, patients can relapse twenty and thirty years later sometimes and whether or not those patients might have been felt to be cured or actually cured versus more or less cured functionally cured from the standpoint of having their disease not recur over their lifespan but whether or not it’s still actually present in their body remains an open question.

So, this trial looked at 110 patients with limited stage follicular lymphoma, essentially treated them all with radiation therapy and used basically circulating tumor DNA and minimal residual disease I should say MRD negative status or – this study took 110 patients with stage I or II follicular lymphoma, treated them all within ball field radiation therapy and used minimal residual disease assessments by what’s called PCR, a highly sensitive molecular analysis to determine if there was any evidence of minimal residual disease in the patient either after radiation or before radiation in order to try to use that MRD status as a potential marker for patients who may be more or less likely to be cured and are more or less likely to have a relapse. And it’s a complicated study design because these patients in some cases depending on their MRD status were treated with additional system therapy with an anti-CD20 antibody ofatumumab.

The bottom line of this trial is that it appears based on the MRD data that despite having limited stage disease, a substantial number of patients still had evidence of minimal residual disease elsewhere, RT alone often was insufficient to eliminate that disease and in fact, of the patients overall, if patients were MRD negative after radiation; meaning having really no evidence of disease that could be seen; this was only long lasting in a subset of these patients and overall, about 20% of patients had both long lasting clinical and MRD negative remissions.

So, this is an important trial because it raises the idea and we’ll come back to this in a few minutes, that minimal residual disease may be an important marker to correlate with long term outcome and who is more or less likely to relapse and may ultimately be a tool that we could use to define who with follicular lymphoma at least in limited stage may be potentially curable or have a long term remission. The techniques of MRD assessment are evolving and we’ll come back to that a little bit later. But I think this is an innovative study to try to use this technology to risk adapt how patients do. I think it’s also sobering in that it suggests that the long term outcomes of patients with limited in stage follicular lymphoma are probably not as high or as favorable with respect to “cure” as we might think based on the fact that a fairly limited minority of patients had a long term clinical and molecular remission in this setting. So, a potential use for novel technology in this setting.

Our next abstract is Abstract 349. This is entitled PET directed therapy for patients with limited stage diffuse large B cell lymphoma. The results of Intergroup NCTN study S1001. This is a National Cancer Institute funded US Intergroup Cooperative Group study led by the Southwest Oncology Group. So, this is a great example and I think demonstrates the value of tac payor funded national clinical trials. This is an important part of our research system that I would encourage everyone to be supportive of because it can really help us answer questions that are the most important medical and scientific questions for patients not necessarily limited or prioritized based on what drug is being used or what treatment is being used.

The concept here is and this was led by Daniel Perske and colleagues from Southwest Oncology Group is focused on the use of PET scanning to define a limited stage diffuse large B cell lymphoma patient population who can receive reduced treatments. So, this enrolled 159 patients with limited stage diffuse large B cell lymphoma stage I or II, certain key groups were excluded because they are managed elsewhere with different regimens such as mediastinal lymphoma. Patients were treated with the standard RCHOP treatment regimen. They then underwent an interim PET scan, and this was administered after several cycles of treatment, after the third cycle of RCHOP. If patients were PET negative, or interim PET negative as defined by their Deauville score, which is a measure of PET negativity or positivity. PET negative meaning Deauville score level 1 to 3. These patients received basically one more cycle of chemotherapy and ended up then being observed. Patients who were PET positive at that interim time point after the third cycle went on to receive additional radiation therapy and received ibritumomab tiuxetan or radio immunotherapy as part of their treatment as well.

So, the take home message of this is that really only 14 out of the 132 eligible patients were interim PET positive so the vast majority of these patients were PET negative. That’s I think a good thing. And the overall patient population did well. The five year progression free survival estimate is 87% and the overall survival is 90% with similar outcomes in the interim PET positive and negative groups so though since there were so few PET positive patients, it may be hard to generalize with out outcomes. And did they benefit from their more intensive treatment. Nonetheless, their outcomes were good as well.

So, I think this study demonstrates that about 90% of patients can have great outcomes with limited stage large B cell lymphoma with RCHOP for four cycles as part of PET directed therapeutic approach. And I think this along with the flyer study that was previously presented at an earlier meeting helps to establish RCHOP for four cycles as being an appropriate regimen for many patients with diffuse large C cell lymphoma in the limited stage setting. There are some nuances to this but in general, many patients may now receive less chemotherapy and do not need radiation therapy with this sort of strategy.

Our next abstract is Abstract 399. This is entitled Incidence of relapse from refractory diffuse large B cell lymphoma including CNS relapse in a population based cohort of 4205 patients in Sweden. Harrison is the first author, Sarah Harrison and this is an interesting population study from the Swedish Lymphoma Registry. Patients with primary diagnosis of diffuse large B cell lymphoma from 2007 to 2014 in Sweden. There were 4200 patients roughly with a median age of 71 years. And this abstract outlined the outcomes of this group of patients. So, I think the value of a registry is that it is obviously a reflective of the entire population of patients or a large population of patients that are generally included in this study.

The take home message of this trial or study, is that the five year cumulative incidence of relapsed and refractory disease in patients treated with curative intent is 23% so, the reality is that almost 80% of patients treated with curative intent have a good outcome and don’t relapse from their disease. This is better – a better outcome than in previously published reports so I think this puts other studies and other studies that are evaluating this population into some context. It also highlights that about 15% of patients could not even start curative intent treatment and another 5% of patients could not tolerate even more than one or two cycles of treatment. So, a high fraction of patients relatively speaking, 15% to 20% are not even really going to be treated effectively.

So I think this tells us that if we’re going to improve outcomes for large cell lymphoma patients; being able to get that 20% of patients to be able to receive potentially curative therapy would be one place where we could intervene. It also suggests that if we’re and we’ve seen this in other studies that if we’re looking at prospectively accrued studies; there is a selection bias. Those patients who can’t get even start potentially curative therapy are not going to go on prospective studies and therefore we have to be very careful as we compare cross studies. Because different patient populations may be reflected to varying degrees based on are these retrospective or prospective evaluations. Additionally, this study reported on CNS relapse. Central nervous system relapse is an important feature that we think about in certain subsets of patients with diffuse large B cell lymphoma. And the incidence of this within two years was less than 10% in this patient population even in high risk patients.

So, I think this is also an important factor that CNS relapse remains a relatively infrequent occurrence and even in high risk groups most patients do not experience this unfortunate event which is obviously a good thing.

The next study that I will present, and review is Abstract 751. This is entitled Minimal residual disease assessment in the ECOG 1411 randomized phase II trial of frontline bendamustine rituximab based induction followed by rituximab plus or minus lenalidomide consolidation in Mantle Cell lymphoma. This is led by Mitchell Smith on behalf of again NCI supported Intergroup trial led by the Eastern Cooperative Oncology Group or ECOG. But again, a national federally funded clinical trial to help establish standards of care for patients in this case with Mantle Cell Lymphoma.

This trial is being presented. Really the interim results, the results of the induction therapy. It enrolled 370 patients between 2012 and 2016 that received either bendamustine and rituximab as their induction treatment or bendamustine bortezomib rituximab as their induction treatment and then patients either received rituximab alone as a maintenance if they responded or rituximab lenalidomide as a maintenance. And so there are four different treatment groups. The focus of this early report is the data on early minimal residual disease assessment. And the concept here has been that MRD negativity or low rates of minimal residual disease have been associated with a more favorable outcome in mantle cell lymphoma and in certain other cooperative group and other trials, MRD positive and negative statuses being used to potentially change therapy.

So, we’re not there at this point in time. The important aspect of this early report is that number one: we know now, and we’ve known from other studies that being MRD negative meaning having absence of minimal residual disease is a more favorable outcome. Those patients do better than those that happen to have residual disease or minimal residual disease at their induction treatment. The other point, however, is that roughly 90% of patients in this study achieved an MRD negative status and so I think that could mean a couple of different things that need to be studied and considered further. One is that bendamustine based therapy is pretty darned good as an initial treatment for mantle cell lymphoma because bendamustine rituximab based therapy gets 90% of patients in an MRD negative state. Which is generally a good thing. Or correlates with a good outcome. The other aspect of this is that using MRD negativity rates as a marker of treatment effectiveness as we compare one versus another induction treatment may be limited because if 90% of patients with the more or less standard BR combination do well and have high rates of MRD negativity; it’s hard to improve upon 90% and we may need other markers to guide us in the future as we develop newer and better therapies.

Now I’d like to move to the next abstract. Abstract 465. This is entitle the combination of oral nanatinostat or NSTAT a novel histone deacetylase inhibitor and the oral antiviral valganciclovir is active in relapsed and refractory Epstein Barr Virus positive B cell, T cell and Hodgkin’s lymphoma. Interim results from a phase I B and II A study. So, this is led by Dr. Pierluigi Porcu from Thomas Jefferson University on behalf of a group of investigators.

The concept here is that there are subset of lymphomas including Hodgkin’s lymphoma and some B and T cell lymphomas that are associated with Epstein Barr virus. And Epstein Barr virus infection being involved in and incorporated into the tumor cells. The idea of targeting Epstein Barr virus which is at least in part a driver of the lymphoma and is generally associated with a less favorable prognosis in certain types of lymphomas make sense that you could target the EBV potentially and that could improve or effectively treat the lymphoma outcome.

So, the issue here is that as Epstein Barr virus incorporates into the DNA of the tumor cells; it’s not really in a form that can be easily targeted with a drug. There are differences between what’s called the lytic and the latent phases and that may affect whether certain drugs can target the Epstein Barr virus. And so the concept here is using this histone deacetylase inhibitor nanatinostat in order to essentially activate various pathways in the EBV downstream of EBV and the idea being that by doing this, we may sensitize the tumor cells to an antiviral based therapy. And so this concept which has really interesting and important biologic bases is essentially trying to make an EBV positive lymphoma more susceptible to antiviral treatment which it isn’t otherwise susceptible to because of the nature of how EBV and EBV status is in the tumor cells normally.

And so, it’s basically combining this H-dec inhibitor with the antiviral agent valganciclovir. So, this was a phase IB study and had a limited number of patients so one needs to be cautious but there were 17 patients evaluable for response 25 treated so again keep in mind the intent to treat, not all patients are evaluable and that needs to be considered in looking at these numbers. That said, the overall response rate was 53% 9 out of 17 patients with 5 out of 17 having a complete response. So, I think this is a very interesting approach and was reasonably well tolerated. Obviously, it’s a phase I trial so the details of that need further study. But it suggests that this kind of combination strategy might be potentially useful in Epstein Barr virus associated lymphomas and these lymphomas have limited other ways of targeting EBV or the EBV in the tumor cells. There have been other approaches such as EBV specific T cells that are being explored and also have early activity, but I think this is an interesting an oral combination that I will be keeping an eye on for the future for this patient population.

The next two abstracts which I will call A and B because they are linked on a similar topic are 429 assessment of cell free DNA in 221 patients with lymphoproliferative malignancies at diagnosis and during follow up and 491, short diagnosis to treatment interval is associated with higher levels of circulating tumor DNA in aggressive B cell non Hodgkin lymphoma. So, the first of these by Dr. Elias Campo from Barcelona Spain expands on work of a variety of groups to look at cell free DNA in the blood of patients with various lymphomas and the concept here is that one could potentially and this has been an are of great investigation that this is an area that one could analyze the plasma cell free DNA that is released by tumor cells in the patient into the patient’s plasma can be analyzed through sophisticated techniques and try to us that to either characterize the tumor by looking for certain mutations or look at the amount of cell free DNA as a marker of how much lymphoma is going on in the patient and basically arguing that if the cell free DNA goes away, the patient is likely to do better. If the cell free DNA does not go away, that correlates with a less favorable outcome. And so, there’s a lot of research going on in this area. It’s not really ready for prime time yet for clinical use but it’s making its way into clinical trials.

This first abstract look at 221 patients with a variety of different lymphoma subtypes. And basically made the argument that and concluded that isolation of cell free DNA was feasible using the techniques that these investigators used in over 95% of lymphoma patients and interestingly and importantly, cell free DNA concentration was associated with LDH level and high risk IPI. And so, this is I think important because LDH or lactate dehydrogenase and IPI are associated with less favorable outcomes. That is associated with higher cell free DNA. So, the important aspect of this is whether or not cell free DNA will give information that is complimentary to the standard clinical parameters of LDH and IPI or whether it is simply redundant and where you see cell free DNA, that’s in people you already know have a less favorable lymphoma and the value of cell free DNA is not going to be much in the way of incremental.

So, I have given you two possible interpretations or outcomes of these findings and I think that will be important to take into account as the cell free DNA field moves forward in lymphoma. The second abstract led by Allogene colleagues looked at this in a different way, but I think a similar finding. Basically showing that the level of cell free DNA in the blood in patients with aggressive non-Hodgkin’s lymphoma is associated with a shorter diagnosis to treatment interval in patients with aggressive B cell lymphomas.

Why is this important? We know that diagnosis to treatment interval is an important correlative marker of how patients do with diffuse large B cell lymphoma patients who have a short diagnosis to treatment interval reflecting the fact that they are sick and therefore need treatment quickly is associated with a less favorable outcome and maybe that’s a little bit counterintuitive because you would think that starting treatment sooner makes people do better but this is more of a correlation that if you have to start treatment sooner, it’s because you are sicker and have a less favorable lymphoma. And you also are more likely to have higher pretreatment circulating tumor DNA levels and so, again, this is like the prior abstract reflecting the fact that maybe CT DNA is redundant to some of our standard prognostic features or maybe it’s complimentary and gives us added information. But our future trials will really need to delve into this a good bit more as we move forward in the future.

Next abstract is 1604 the prevalence and impact of hypogammaglobulinemia in newly diagnosed untreated diffuse large cell lymphoma. This is led by Namrata Singh, senior author being Brian Link. This is work from the University of Iowa and Mayo Clinic’s SPORE Molecular Epidemiology Resource which has been a major and important contributor to lymphoma research nationally over the last several years. This looked at frozen sera from 200 newly diagnosed treatment of diffuse large B cell lymphoma treated as part of this cohort. And found – asked the question what is the prevalence of hypogammaglobulinemia basically low serum immune proteins or gamma globulins in this patient population. This has been studied before in chronic lymphocytic leukemia but not so much in diffuse large B cell lymphoma.

What these investigators found is that roughly 20%, 22% to be precise of this cohort had hypogammaglobulinemia when they were newly diagnosed. This may represent an underlying immune issue that has something to do with the patient’s lymphoma. It may also represent that they might have an immunodeficiency state that might have not previously be detected. And may result in or correlate with infections that this patient population may have.

But nonetheless, 22% I think is a meaningful number. It also showed that this group of patients had a less favorable outcome and again, how this is connected to lymphoma outcome, I think needs to be explored but suggests that we might want to be looking at gamma globulin levels even before treatment and that this might be an important factor in the patient’s outcome or at least correlate with the patient’s outcome as well as potentially their infection risk. So, more to come here but I think an important new insight from a very important resource in lymphoma research that being this group that I alluded to.

Next, we’ll turn to abstract 122 evaluation of the M7-FLIPI patients with follicular lymphoma within the gallium trial.  EZH2 mutation status may be a predictive marker for differential efficacy of chemotherapy. Some aspects of this have been previously presented but this trial looked at 1200 patients with follicular lymphoma receiving rituximab or obinutuzumab plus chemotherapy which could have been CHOPS, EVP of bendamustine as their initial treatment for follicular lymphoma. The question that’s being looked at here is the concept of the M7-FLIPI or the molecular version of the follicular lymphoma international prognostic index and are there features of the M7-FLIPI that could be used to guide therapy or to predict outcome beyond the M7-FLIPI which we know has a correlation with the outcome of the patients.

So, this trial looked at the M7-FLIPI in this group of patients and identified 104 patients with high risk M7-FLIPI treated on this trial and the net or the key new insight here is that EZH2 mutation status is one of the findings that is associated with follicular lymphoma patients in their tumors. It’s a minority of patients but nonetheless and easily detectable mutation in this patient population using some of the newer testing. And EZH2 mutation is interestingly associated with a longer progression free survival in patients receiving CHOP based therapy or CVP based therapy but not with patients treated with bendamustine based treatment.

So, there are a lot of caveats to this study that I don’t have time to go into, but it at least raises the idea that one should use an EZH2 mutation status to decide whether or not it’s better to treat a patient with a CHOP based regimen or a bendamustine based treatment regimen in the future. And we’re not there yet so I wouldn’t use it in my practice, but I think it’s something that would be nice to be able to use a mutation marker to help us choose therapy if in fact it was validated and was associated with a better outcome with a particular treatment. And I’ll just mention that we do have a drug tazemetostat also being reported on at the ASH meeting which has activity. It’s an EZH2 inhibitor that has activity in follicular lymphoma and that activity occurs both in mutated EZH2 mutated follicular lymphoma possessing patients as well as non-mutated patients although the drug works better in the mutated patient population. So, I think we’re moving toward using EZH2 status as an important tool in the not too distant future for patients with follicular lymphoma.

I’ll conclude the “standards” before we get to the bonus components of the Leonard list with two abstracts. We’ll call them A and B again. The first is abstract 1615 a risk of fracture following frontline RCHOP immunochemotherapy in older patients with diffuse large B cell lymphoma is common. This is from a group based in the UK particularly at Oxford and also abstract 4124 entitled bone loss and high bone turnover in patients with non-Hodgkin’s lymphoma who receive frontline chemotherapy, final results of a multicenter prospective study.

So, the first study looked at a group of consecutive patients almost 600 patients over the age of 70 or 70 or older treated with RCHOP retrospective analysis and asked the question what is the fracture rate in these patients, getting at their bone loss concerns base don obviously age and treatment as well as other factors. It found that over the course of the follow-up period in this particular study that there was essentially a cumulative incidence of fractures of various types at 6.3% at six months and when you go out to 18 months 11.5%. so, roughly 10% of patients of this population had a fracture at various sites within a year and a half. And that, to me seems pretty striking.

At least anecdotally it seems less or more common than I have remembered at least in my practice. It may reflect the fact that we as oncologists don’t always appreciate or identify or deal with these issues for our patients, but it also highlights the issues around bone health for our patients who have received treatment for diffuse large B cell lymphoma and particularly RCHOP therapy. The compliment to this study, the second abstract not designed as a compliment but functionally as a compliment looked prospectively at 61 patients with newly diagnosed NHL and looked at various markers of bone turnover and suggested that first line immunochemotherapy and often this was RCHOP for this group of patients results in high bone turnover, increased bone loss and reduced bone mineral density.

So it again, supports the idea that bone health is important, fracture risk, osteoporosis risk is important in this population. I think this is something that we need to be aware of as we treat our patients and need to prospectively evaluate the value of interventions that may minimize or prevent this complication for our patients as part of their survivorship programs.

So, in the last couple of minutes of this program, I’m just going to quickly give you some thoughts on the five bonus abstracts. First Abstract 151 Longitudinal assessment of circulating mutational burden using a next generation sequencing cancer gene panel, a potential biomarker response to program cell death on for PD1 blockade in patients with relapsed refractory classical Hodgkin’s lymphoma. This study looked at patients with again, Hodgkin’s lymphoma, a large number of patients looking at – a small number of patients a large number of genes but basically, looking at markers for various gene mutations that have been associated with classical Hodgkin’s lymphoma. It basically suggests that in this patient population, you can detect gene mutations in circulating tumor DNA and that the pattern on mutations whether they are resolved or persistent correlates with outcome of the patients to therapy primarily in this case again, PD1 inhibitors or immune checkpoint inhibitors. So, I think this is a study that suggests that again this may be an important technology that can help track how patients do and potentially in the future, help to guide therapy. Again, here focusing this study on classical Hodgkin’s lymphoma and immune check point inhibitors.

The next bonus abstract is 761 a phase II trial of the IR2 regimen or a ibrutinib, lenalidomide and rituximab in patients with relapsed refractory non-germinal center like or non GCB diffuse large B cell lymphoma. This is a multicenter phase II trial with 89 patients so a pretty substantial patient population looking at this combination of drugs. Lenalidomide and ibrutinib which have been as we talked about earlier suggested to have activity in this non-germinal center subset of diffuse large B cell lymphoma as well as rituximab. This trial as you would expect, with this combination of drugs had some adverse events which are important to keep in mind including GI toxicity, fatigue, cytopenia, rash, so it’s not a totally easy to tolerate regimen. But that said, had in a fairly resistant patient population an overall response rate of 47% including 28% CRs, 19% with partial responders and in 40 responders, the median progression free survival was 21 months and so, it suggested there’s a population of refractory large cell lymphoma patients with this profile that could have a durable remission to this combination of drugs.

It suggests like we are learning that CAR-T cells aren’t the only things out there that can give you a durable response in relapsed or refractory diffuse large B cell lymphoma. There are other things whether they are bispecific antibodies, antibody drug conjugates or combinations of targeted drugs that can also do the same thing and obviously the question is well which patient subset benefits from this treatment versus other treatments.

Our next bonus abstract is 3997 a short time to treatment is associated with inferior survival in newly diagnosed patients with mantle cell lymphoma. This is a multi-institutional group that evaluated 1168 patients, so a huge group of mantle cell patients newly diagnosed and evaluated the time to treatment again we alluded to this earlier the concept being that if you need to be treated quickly, that is associated with a less favorable outcome because you are so sick that you need to start treatment earlier and so this looked at a group of patients who were treated quickly within 14 days primarily although they looked at other timepoints, and essentially as we saw in large cell lymphoma and other settings, that a short time to treatment interval for newly diagnosed mantle cell patients is associated with aggressive disease features and an inferior overall survival. So, this again, highlights the importance of time to treatment for newly diagnosed patients as a prognostic feature that we should keep in mind as we look at trials and also design trials.

Next abstract 3995, also focusing on mantle cell lymphoma looks at high TP53 mutation load predicts primary refractory mantle cell lymphoma. This is an important study. The concept of TP53 mutations being associated with an unfavorable outcome in intensively treated patients with mantle cell lymphoma. This was established by a group studying the Nordic regimen an intensive approach suggesting that if you had a deletion of P53, that this was less good as far as your outcome and if you had a mutation of P53, when you were diagnosed, you had an even less favorable outcome with an intensive treatment approach and this report looked at 115 patients treated at Check Centers and this group of patients were treated particularly with an RCHOP or an intensive regimen or another regimen so a variety of different intensive or less intensive regimens but look at P53 mutational status and I think confirmed the idea that P53 mutations and in particular, a high burden or a high load of TP53 mutations is associated with a particularly less favorable outcome with regard to overall survival. So, this remains a subset of mantle cell patients where we need to be thinking differently and where we need to continue to focus our research strategies.

Finally, abstract 2824 the last of our bonus selections. Bendamustine rituximab does not improve survival over rituximab monotherapy for older patients with nodal or splenic marginal zone lymphoma. Marginal zone lymphomas are indolent lymphomas that have obviously a particular distinct characteristic features as well as biologic features. This study looked at Medicare claims data linked to cancer registries and identified over 1300 patients, 900 who had nodal marginal zone lymphomas and 414 with splenic marginal zone lymphomas. Importantly, the median age was 78 in this group of patients, so an older group of patients and the question here was that we know that bendamustine rituximab is a reasonable treatment for this group of patients. We also know that rituximab as a single agent is a reasonable treatment for this group of patients.

In my practice, the choice of rituximab or bendamustine rituximab is a common question that we are faced clinically with as we encounter and choose therapy for this group of patients. And what this obviously, retrospective registry based data suggests and again, a large number of patients is that the event free survival and overall survival was similar whether or not patients were treated with single agent rituximab or bendamustine rituximab as their first line treatment. So, this is not a randomized trial, obviously there are selection features that went into the choice of treatment here but nonetheless, I think suggests that there’s probably not a downside if you choose rituximab as a single agent to go ahead and do that because it’s not clear that bendamustine rituximab based therapy is superior or rituximab in this patient population.

And so I think this is an important and reassuring practical issue, practical report for those of us who treat splenic marginal zone patients. Again, this was focused primarily on the older patient population.

So, with that, we’ve completed our rundown of the 2019 Leonard list for the American Society of Hematology Meeting. I hope you found this of interest. And I look forward to feedback from this list and this discussion. I hope you will follow us on Twitter and take a look at these abstracts in more detail and feel free to comment on them. I hope that you’ve also found this summary as well as our bonus selections to be particularly helpful and useful to get this information a little bit different way. And again, I look forward to feedback and further discussions with many of you about these and other data at the ASH meeting.

I also want to invite you to download, subscribe, rate and review CancerCast on Apple Podcasts, Google Play Music or online at www.weillcornell.org. We also encourage you to write to us at cancercast@med.cornell.edu with questions, comments and topics you’d like us to 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.