Transcription:
Leonard List 2018

Dr. John Leonard (Host): Welcome to Weill Cornell Medicine CancerCast: Conversations About New Developments in Medicine, Cancer Care, and Research. I'm your host, Dr. John Leonard, and today is an episode that I've been looking forward to for a while. We are going to review this year's Leonard's List, and the Leonard List is a list that I started several years ago on Twitter counting down through the ten days before the American Society of Hematology meeting, the ten most interesting or important abstracts in lymphoma or abstracts that just got my attention that are going to be presenting at the upcoming meeting.

And so what we decided to do this year in addition to our Twitter countdown was to actually give you a preview of this year's Leonard's List. So in the Leonard List what I've done is basically looked at abstracts that got my attention and that were of interest and kind of put them out there, and they're really there for people to think about, maybe things that people missed as they looked at the abstracts, and certainly there are patients and others in the field that may have their own opinions, and sometimes that leads to dialogue on Twitter or elsewhere. So we're happy to have some dialogue about some of the new data coming out at the ASH meeting.

For those of you who are less familiar with ASH, ASH is the world's largest professional society that serves clinicians and scientists who work to cure, manage, and understand blood diseases. Every year for the past sixty years, ASH hosts an annual meeting, and this is a gathering of more than 25,000 hematologists from across the world that discuss the latest research and discoveries in hematology and really gather to interact, to present data, to talk about new findings, and also to build collaboration.

And if you'd like to reference these individual abstracts that we'll go through today, you can take a look at my Twitter following, @JohnPLeonardMD, and that's where over the course of about ten days I will again provide some written comments and also links to all of the individual abstracts that we'll talk about today.

And one of the things that we also are doing in this episode is that we decided since we have a little extra time for our listeners, we'll have five bonus abstracts that I'll get to at the end, so actually the Leonard List will be fifteen abstracts for those of you listening on our CancerCast podcast, and so you'll have a little extra insight, and a little extra thought beyond the typical ten.

So I'd like to go ahead and jump right into this year's Leonard List ASH Abstracts, and so we'll just go ahead and start the countdown, and I'll give you a few comments on each of these that got my attention.

So the first of these, number ten - we'll count down backwards - is abstract 679. The first author here is Catherine Diefenbach from NYU. This is entitled, 'A Phase I Study with an Expansion Cohort of the Combinations of Ipilimumab, Nivolumab and Brentuximab Vedotin in Patients with Relapsed/Refractory Hodgkin Lymphoma: A Trial of the ECOG-ACRIN Research Group (E4412),' and this is really a study that is looking at - as the name implies - a combined treatment of immune checkpoint inhibitors as well as the anti-CD30 antibody drug conjugate Brentuximab Vedotin in patients with relapsed Hodgkin Lymphoma and Refractory Hodgkin Lymphoma.

So E4412 was a study that basically looked at and established doses of Nivolumab and Ipilimumab, or Ipi, that are immune checkpoint inhibitors in combination with Brentuximab Vedotin, and what's being presented in this abstract is really some early data on safety and efficacy, and there were twenty-two enrolled patients in the early part of this study. You can see the details in the abstract if you like. Toxicities were, as one might expect, a number of skin toxicities being most common (rashes), and some autoimmune phenomena; colitis, diarrhea, et cetera. These seem to happen largely in limited numbers of patients, but again, it's a phase one study. There were basically- overall the doses were established for this treatment regimen, and interestingly the overall response rate for the full population was 82% with a complete response rate of 68%.

And so I think this is an interesting study, it's an interesting combination, obviously using an antibody drug conjugate in combination with an immune checkpoint inhibitor is something that is of interest, and I'm happy to say that this study is expanding in the intergroup. I happen to be part of the Alliance Lymphoma Committee, we are collaborating with ECOG-ACRIN as is the Southwest Oncology Group, and so this study is expanding with larger numbers of patients and is available in many centers across the country.

So again, an interesting abstract looking at potentially a new regimen that has activity and reasonable tolerability in relapsed Hodgkin patients that may go on to other disease settings including potentially the pre-transplant setting and the relapsed situation, and obviously immune checkpoint inhibitors are being looked at in a variety of different Hodgkin Lymphoma settings, as well as obviously solid tumors.

Our second in the countdown, or number nine overall as we count down backwards, is abstract 2873. This is Ciara Freeman out of the BC Cancer Agency is the first author. This is a poster, again 2873 entitled, 'Frontline Therapy with Bendamustine and Rituximab (BR) in Follicular Lymphoma: Prognosis Among Patients with Progression of Disease By 24 Months (POD24) Is Poor with Majority Having Transformed Lymphoma.'

So we've learned in follicular lymphoma that early progression, particularly after chemo immunotherapy within two years of initial treatment, is associated with a less favorable prognosis. And these data have largely come from patients treated with R-CHOP or R-CVP chemotherapy. And what this study did was it looked at the BC lymphoid cancer database, identifying patients treated with Bendamustine and Rituximab with follicular lymphoma, identified about 300 patients, and basically sought to look at the outcomes of those patients who progressed within twenty-four months. And again, this is looking at this particular early progressor cohort after BR.

And the net of this study is that early progression occurred in about 12% of patients. That's perhaps a little bit less than what we've seen in some of the other cohorts, thirty-five patients, and I think the important aspect of this was that the majority of the early progressors after BR, 77% of these early progressors has transformed lymphoma. And the net is that this group of patients had a relatively unfavorable outcome, even worse than those that progressed after other regimens from other studies. The BR treated patients with POD within twenty-four months was poor with overall survival being just under 40%.

So this really suggests a couple of things. Number one, that patients treated with BR and having early progression perhaps need to be - probably should be - considered for other therapies. There's an intergroup study led by the SWOG that's looking at a number of different regimens for this patient population; PI 3-kinase inhibitors, other chemotherapy, as well as Lenalidomide based treatment. But also that the majority, the vast majority of these patients had transformation, and so I think that really tells you that you need to, if you see a patient with early progression after BR, be especially concerned or heightened attention to the possibility of transformation, doing a biopsy because obviously that will change therapy, and can be associated with a less favorable prognosis, at least in this cohort.

Number eight in our countdown, as we go down backwards, is abstract 1605. This is led by my colleague, Sarah Rutherford at Weill Cornell, and it's entitled, 'Bone Marrow Biopsy Impacts Response Assessment in a Minority of Patients with follicular lymphoma and Diffuse Large B-Cell Lymphoma Treated with Immunochemotherapy: Results from the Randomized Phase III GALLIUM and GOYA Trials.'

And so Dr. Rutherford has been interested in the role or lack of role of bone marrow biopsies in studies of follicular lymphoma and other lymphomas in response assessment. As many of you know, bone marrow biopsies are commonly performed as part of clinical trials where patients are staged and to establish whether or not the patient may have had a complete response after therapy. And we hypothesize that really this was not very valuable, that the place where bone marrow biopsies made a big difference in outcome of response assessment was likely to be pretty small.

If you look at the number of patients that had a positive bone marrow, went into a CR, and then the bone marrow is what changed the subsequent response assessment, either away from a CR or confirmed a CR, we hypothesize that bone marrow biopsies were not very helpful. And Dr. Rutherford had looked at a small series from our own patients at Weill Cornell with follicular lymphoma, and essentially showed that this point was in fact the case, and that bone marrow biopsies had limited utility. She now with her collaborators looked at 1,200 patients from the GALLIUM study with follicular lymphoma, and also in the GOYA study had a large number of patients here, over 1,400 patients.

The net of this analysis was that in the follicular lymphoma study, about half of patients had a positive bone marrow at baseline, but after treatment the reality is that the repeat bone marrow was only relevant for under 1% of the patients in establishing the response and confirming the response.

In the GOYA trial looking at DLBCL patients, only about 10% of patients had a positive bone marrow. And again, bone marrow results only affected a response, again, under 1% of all enrolled patients. And so this study really I think confirms the lack of importance of bone marrow biopsies in response assessments here in both follicular and large cell lymphomas, in that the bone marrow biopsies affected the response criteria in less than half of 1% of all enrolled patients.

And so this really suggests that we can avoid the time, the expense, the discomfort of doing bone marrow biopsies in clinical trials, and I really hope that this will lead to the field, and researchers not building bone marrow biopsies into clinical trials in lymphoma unless there are really other reasons for doing so beyond response assessment in the clinical trial.

Our next abstract, number seven, is abstract 683, and this is led by Steve Horwitz at Memorial Sloan Kettering Cancer Center and colleagues. This study looked at the combination of Duvelisib, which is a PI3-Kinase Delta Inhibitor, and Romidepsin in patients with Peripheral T-Cell Lymphoma. So Duvelisib is the third approved PI3-Kinase inhibitor in lymphoma. It's approved predominantly in follicular lymphoma, also in CLL, and the net is that Duvelisib hits and goes after the delta and gamma isoforms of PI3-Kinase.

It also has had activity in other studies in T-Cell lymphomas, where standard therapies in relapsed and refractory T-Cell lymphomas have roughly a 25% to 30% response rate.

So this study combined Duvelisib with Romidepsin. Romidepsin is a histone deacetylase inhibitor also approved in recurrent peripheral T-Cell lymphomas. In this phase one trial, the doses were established, there were some transaminases as part of the toxicity profile. Other toxicity profiles included cytopenias, and a few other toxicities associated with these drugs given separately including diarrhea. And the net of this, remembering it's a phase one trial, was that the overall response rate to this combination in thirty-five patients with peripheral T-Cell - well, with T-Cell lymphomas across the board, was about 51% including six CRs across the board and twelve PRs.

And so the net is that I think the Duvelisib Romidepsin combination is one that warrants further studies, and I think we're going to see more of this. The study also looked at Duvelisib plus bortezomib, the proteasome inhibitor and had less activity there. But again, this suggests that the combination of a histone deacetylase inhibitor and a PI3-Kinase inhibitor might have value certainly worthy of further exploration in clinical trials in patients with a variety of different T-Cell lymphomas, and we'll see where that combination goes in the future.

Our next abstract is abstract number six in our countdown, going down backwards, and it's abstract 681 led by Natalie Grover and colleagues from the University of North Carolina, and this is entitled, 'Clinical Responses to CAR.CD30-T Cells in Patients with CD30+ Lymphomas Relapsed after Multiple Treatments Including Brentuximab Vedotin.'

This audience certainly knows the CAR-T cell, or Chimeric Antigen Receptor Modified T-Cell, field well. We have a couple of different CAR-T cell products that are FDA approved for lymphoid malignancies, however those tend to target CD19 which is a B-Cell antigen and so one of the interesting areas is obviously to try to bring new targets into the fold for CAR-T cells, and one of those is CD30 which is present on obviously CD30+ Non-Hodgkin's lymphomas, and in Hodgkin lymphoma on Reed Sternberg cells.

So this is a CAR-T cell that targets CD30 and then codes the CD28 endodomain, and so there have been early data with this, and other constructs. This was a trial that it was a phase one B2 trial giving lymphodepleting chemotherapy followed by, again, CD30 CAR-T cells. I think this is an interesting area that is moving kind of on the heels of the CD19 directed CAR-T cell therapy.

This abstract included a group of patients, there were eighteen patients, four of whom were in complete response when they went into the CAR-T cell therapy because they had received bridging chemotherapy. And then there were fourteen patients who still have evidence of the disease. Of these fourteen patients, six had a CR. These were 43% of the group. These were in people that had received Benda fludarabine lymphodepleting chemotherapy.

Overall, the progression for survival median was relatively short, reported to be in the range of about 120 days or so, however two out of fourteen evaluable patients were still in CR at one year, and there were a number of different technical parameters reported as well as along the lines of cytokine release and persistence of T-cells being reported.

And so I think this is an interesting relatively early step in CD30 directed CAR-T cell therapy. Also it gives some data on the use of lymphodepleting chemotherapy, and obviously I think we will hear more and see more of this approach using, again, modifications and evolution of the preparative lymphodepleting regimen, as well as optimizing the dose of CAR-T cell treatment, as well as ultimately combinations I would assume. And one would envision, given the interest in immune checkpoint inhibitors in Hodgkin’s and the interest in immune checkpoint inhibitors in combinations with CAR-T cells, that at some point in the future we'll see that combination emerge in this particular setting.

Our next abstract, number five in our countdown, is abstract 2911. This is from Reddy- Reddy and colleagues, a multi-center group but essentially based at the University of Washington in Seattle at Fred Hutchinson Cancer Center, and this is entitled, 'Eligibility for Car-T Cells: An Analysis of Selection Criteria and Survival Outcomes in Chemorefractory DLBCL.'

This got my attention because of an interest and various discussions and interactions with colleagues thinking about selection biases in CAR-T cell therapy. This is a study that basically looked at the center - and Seattle is obviously a very large center that has been very active in CAR-T cell therapy - looking at patients with DLBCL seen there, and looking at those receiving CAR-T cell treatment, and those that were not eligible for CAR-T cell treatment.

And basically there were about 400 patients in the database, and what was looked at and evaluated was the various populations of patients that were ineligible for or that did not receive CAR-T cell therapy to try to get a sense of how these patients did.

And the net is that roughly 50% of patients in this group that were patients that had chemorefractory disease and would otherwise potentially be candidates for CAR-T cell treatment, about 50% of the patients were ineligible, and the issues around eligible patients having better outcomes than ineligible patients was of interest. Obviously one could interpret this as the fact that those eligible patients received CAR-T cells, and potentially did better in some cases.

However, those that were ineligible included those who had acute therapy- a need for acute therapy for rapid disease progression and impaired performance status and non-follicular transformation. And so this again I guess highlights the issues around trying to broaden eligibility to help those patients who are not going to do as well, and also highlight the issue of patient selection in clinical trials, which I think in the CAR-T cell literature is very important to keep in mind because of the fact that these are to date largely non-randomized trials, and so we're comparing to historical data, and obviously these comparisons and the outcomes are going to be influenced by the patients that find themselves eligible for these trials, and therefore on the other hand when lots of patients or substantial numbers of patients are excluded, obviously the patient selection is going to influence the outcomes that are seen independent of the effects of the therapy itself.

Our next abstract is led by Shanmugasundaram and colleagues from Emory and representing a multi-center group. This is abstract 4153, 'Intensive Induction Regimens after Deferring Initial Therapy Are Not Associated with Progression-Free or Overall Survival in Patients with Mantle Cell Lymphoma (MCL).' This is abstract number four in our countdown, and it seems like every year the Emory group here led by Jonathon Cohen as Senior Author has some interesting insights often around mantle cell lymphoma that I find of interest for the Leonard List, so this year is no exception.

And this is an abstract that really looked at an issue that we've been very interested in, and my colleague Peter Martin really I think was the first among many subsequently who have identified the potential ability to watch and wait in mantle cell lymphoma and defer therapy, and it's interesting- there was another abstract I didn't include in the Leonard List but I came across in the ASH abstracts that suggested that more and more watch and wait or observation with deferred initial therapy seems to be entering the standard practice. More and more patients seem to be observed than perhaps in the past, which is perhaps a result of the data that are coming out suggesting that this is okay to do.

So in any event, this particular abstract looked at 968 patients with mantle cell lymphoma in a large group of eleven academic centers, and 233 of these patients did not initiate therapy within ninety days of diagnosis and were considered deferred as far as having deferred therapy.

What this group did was then go on and look at what therapy these patients ultimately received when they received treatment, and basically compared the outcomes of those patients who received non-intensive therapy versus intensive therapy, intensive treatment largely being transplant-based regimen, and non-intensive treatment largely being R-Bendamustine and R-CHOP. And so the net is that the overall survival and progression-free survival was similar in this group of patients who deferred therapy, ultimately received therapy. The use or lack of use of an intensive induction therapy did not seem to improve overall progression-free survival.

And so this is interesting in my mind. The value of intensive treatments is something that remains questionable with regard to overall survival. One might argue that patients who are observed for a period of time might have more favorable disease. Certainly they do, but when they ultimately need therapy, presumably their disease has gotten worse and has indications for treatment, and these data suggests that how you treat these patients really doesn't matter with regard to overall or progression-free survival.

So obviously there are biases and different factors that could influence this, but it certainly also suggests that this may be a different patient population and as these patients go on to clinical trials, that they may reflect a different population than those patients who need initial treatment. And in fact, there's another abstract led by Matt Maurer and colleagues that I was happy to participate in with colleagues suggesting that time to treatment in mantle cell lymphoma, longer time to treatment tends to correlate with better outcomes. So this study may also be an ultimate reflection of that phenomenon; I.E. patients that are not ill who can defer therapy for a period of time tend to do better.

Next in our countdown, our third abstract in the countdown, is abstract 1682. This was led by Michael Dickinson and colleagues from Melbourne, Australia, and as well as an international group of collaborators. This is abstract 1682, 'A Phase I Study of Molibresib (GSK525762), a Selective Bromodomain (BRD) and Extra Terminal Protein (BET) Inhibitor: Results from Part 1 of a Phase I/II Open Label Single Agent Study in Subjects with Non-Hodgkin’s Lymphoma.'

So there are a number of novel targets under investigation for Non-Hodgkin's Lymphoma obviously. Molibresib, which also has this long GSK number, is a potent and specific inhibitor of the bromodomain and extra terminal domain or BET family of proteins, and when you inhibit this family of proteins, this interferes with transcriptional complex assembly and expression of a number of oncogenic drivers. And so there is extensive pre-clinical data with this agent, and this was really the NHL dose escalation cohort from a study in patients with relapsed and refractory hematologic malignancies.

And so the authors report on twenty-seven patients with NHL with relapsed or refractory disease. They had a variety of different lymphomas, mostly B-cell lymphomas as you would expect, median of three prior regimens. This is an oral drug given once daily, and basically there was a dose escalation cohort here. The findings of this study I think were interesting. One patient with DLBCL had a complete remission. Four additional subjects - one with DLBCL, one with CTCL - had partial remissions, and the overall response rate was 18.5%. There were a number of other patients that had stable disease. Toxicities included thrombocytopenia, fatigue, nausea, and rash, as well as a few other toxicities that were reported.

And so I think this is interesting because this is an interesting and important target in Non-Hodgkin's Lymphoma. It seemed to be a manageable toxicity profile. The recommended phase two dose was identified. There was significant activity, particularly in CTCL, and I know that this agent, as well as others that are going after the same target, will be studied further in the future, and I think this is a target, an agent, as well as a class of drugs that will be potentially something that we hear more about in the coming months and years.

Abstract number two in our countdown is abstract 2974. This is led by Stephanie Teja and colleagues from Wash U. in St. Louis, and this is abstract 2974, 'Sex Differences in Visceral Fat Measured by CT or Computed Tomography Helps to Predict Progression Free Survival in Patients with Diffuse Large B-Cell Lymphoma.'

And this got my attention because patients with DLBCL obviously are always or often concerned about risk factors, they're often concerned about what they can do to decrease their recurrence risk, and like in many other malignancies, we're learning more and more that obesity is a risk factor for a variety of cancers including pancreatic cancer, paracellular cancer, renal carcinoma, breast cancer. And this group has looked at visceral obesity using a relative visceral fat area calculation using CT scanning, and the bottom line is that this group evaluated a large number of patients - 156 patients - with DLBCL that were diagnosed and treated at Wash U. at St. Louis, and the two-year overall survival of this cohort was 86% progression-free survival. About 80%, again, perhaps a fairly representative outcome overall for this group of patients at an academic center.

And what they did was then go and look at BMI, and look at this parameter of rVFA, basically a measure of visceral fat- relative visceral fat area. And the net of this report is that elevated rVFA, or essentially more visceral fat, was associated with a higher risk of progression in women with DLBCL, not associated with a worsened prognosis in men, and basically this again suggests that as in other malignancies, sex and fat metabolism may play a role in DLBCL prognosis.

And there have been other studies that have suggested that obesity is associated with prognosis in various cancers including lymphoma, and I think it provides more data to raise issues around tailoring of therapy, supportive care, expectations as far as outcomes or stratification in clinical trials, as well as the potential that weight loss for patients might affect outcomes. And obviously these are associations at this point, so we would need to prospectively test whether or not any specific interventions would impact this effect, if in fact this effect is not just an association but causation.

But I think it's an important area to highlight with our patients, and certainly suggest that one might want to consider this issue in more detail as we look at patients with large cell lymphoma and think about lifestyle modifications and other issues that could affect their outcomes ultimately.

The last abstract in the Leonard List for ASH 2018, and we'll get to our bonus five abstracts in just a minute, but our last in our official listing of abstracts is abstract 926 by Boell and colleagues. Dr. Boell is representing the German Hodgkin's Study Group and a number of different colleagues participating, as well as the Nordic Lymphoma Group. This is abstract 926 entitled, 'B-CAP (brentuximab vedotin, cyclophosphamide, doxorubicin and predniso(lo)Ne) in Older Patients with Advanced-Stage Hodgkin Lymphoma: Results of a Phase II Intergroup Trial By the German Hodgkin Study Group (GHSG) and the Nordic Lymphoma Group (NLG).'

So as it's getting increasing attention, there are about 20% of patients with Hodgkin's Lymphoma are older, aged sixty or older, they've been associated- their outcomes have been associated with a poor prognosis, particularly with advanced stage disease. This in part relates to the disease itself, it in part relates to toxicity, particularly issues with bleomycin, and issues with bleomycin in older patient populations and excess toxicity.

In ABVD treated patients and other abstracts suggest that substituting brentuximab vedotin for bleomycin may not have a major impact in this older patient population, although those data are still being generated, and some data from that are being reported by Andy Evans and colleagues at the ASH meeting this year. The GHSG in combination with the collaboration with the Nordic Lymphoma Group decided to prospectively evaluate in a multi-center phase two study, substituting brentuximab vedotin into a CHOP-based regimen with, again, this B-CAP regimen in older patients.

This was a group of patients over age sixty, and the net of this study was that it enrolled fifty patients, they largely had advanced stage disease. The median age was sixty-six, so a fairly unfavorable prognostic group, and the net is that the overall response rate was 98%. Twenty-one patients had a CR, twenty-six with a PR, one progression of disease patient, and again, the majority- well, about half of the patients with a PR had a negative PET scan. So the complete metabolic response rate was about 65% and obviously at this point more follow-up is needed for the durability, and this will be presented at the meeting.

But the net is that this seems to be a feasible regimen for older patients with Hodgkin's Lymphoma and incorporates brentuximab vedotin and it's a CHOP-based type of regimen without vincristine. And so I think there's been a lot of attention to older patients with Hodgkin's Lymphoma, and exactly what the best regimen is, I think we've largely are moving away from ABVD, but I think we're starting to have a couple of different candidate regimens for this group of patients, and hopefully we can get some comparative data to try to better establish an optimal regimen for this patient population, and certainly the B-CAP regimen given that it's been tested in a multi-center prospective trial, among other regimens may warrant I think further evaluation in the future.

So that brings us to the end of our formal Leonard List, but since all of you have tuned in and heard some of my discussion points about this year's selections, obviously ASH has thousands of abstracts, and there are hundreds on lymphoma, so I just wanted to very quickly give you kind of five bonus selections, and I'll just very quickly give you a few comments on some of these. Obviously there are many that are being presented at the meeting, but I wanted to highlight a few of interest and of some practical value, particularly if you're paying attention to the field, paying attention to new drugs, and treating patients in your practice.

So very quickly, our five bonus selections, the first of which is abstract 2883. This is from Matt Davids and colleagues from Dana Farber, and this is, 'Long-Term Follow-up of Patients with Mantle Cell Lymphoma Treated with Venetoclax Monotherapy.'

As you know, Venetoclax is an oral inhibitor BCL-2. It's approved for CLL and has activity in mantle cell lymphoma. This is a longer term follow-up report for twenty-eight patients with mantle cell lymphoma. We know that Venetoclax has been active in MCL, it's being looked at in combinations with other drugs such as Ibrutinib. And the net of this report was that the overall response rate in these twenty-eight patients was 75% and at this point the median progression-free survival is eleven months, a two-year progression-free survival of 30%.

So it's a small study. This study was done as part of a larger study some time ago, but what I think is of value is some information on the durability because while Venetoclax is not approved in mantle cell, certainly I think it's an agent that warrants further evaluation in mantle cell, both alone and in combination, and now we have a little bit of data on the durability to base some of these interpretations on.

Next I wanted to highlight abstract 223, 'Late Effects of CD19-Targeted CAR-T Cell Therapy.' This is, again, from the Fred Hutch Group and elsewhere, Cordeiro and colleagues. And the net of this was to characterize fifty-nine patients with relapsed and refractory NHL and CLL who received eighty-five CD19-Targeted. So some patients had more than one CAR-T Cell Treatment, and had survived more than a year, and had at least one year follow-up.

So the question is what are the long-term outcomes as far as late effects and side effects? And there's a nice summary of this in this abstract. I think this is useful. Obviously this is a complicated analysis because all of these patients have had extensive prior therapy, and so when you look at late effects, it's hard to know what of the late effects are from the CAR-T Cell Therapy versus the other prior therapy that these patients would have received.

And so there were a number of different adverse events that this patient population had had. I think it's a reasonable reference for patients getting CAR-T cells. Obviously many of these patients have such chemorefractory disease that late effects is really a secondary consideration as opposed to the primary disease control, but having some data on what's seen later is of interest and importance.

And I think the thing that struck me with this abstract was that there were- of fifty-four patients, there were 178 suspected infection events beyond day ninety after CAR-T cell infusions in the majority of the patients. And so infections are an issue. I think we're learning more about this. There are some questions around immunoglobulin deficiency and need for IVIG, but in these infections, about half the patients had required hospital admission due to infections, and 15% of them were infections that then required ICU admission.

So the point being that infections seem to be a late finding in CAR-T Cell Therapy. Again, what this is due to, whether it's the CAR-T cell itself, or the combination of that with prior therapy remains to be seen. But we really do need to- if this is going to be used more commonly, need to characterize long-term effects and obviously be prepared to deal with and manage or prevent infections as appropriate.

Next I wanted to highlight abstract 93. This is from Carreau and colleagues from NYU and elsewhere. Abstract 93 looked at, 'Checkpoint Blockade Therapy May Sensitize Aggressive and Indolent Non-Hodgkin Lymphoma to Subsequent Therapy.'

And this is a little bit of a confounded analysis, but it's an interesting concept looking at seventeen centers across the US and Canada. 121 lymphoma patients, and forty-two of them who received further therapy after having previously received checkpoint blockade therapy, and there were a number of different treatments; chemotherapy, targeted chemotherapy, chemo clinical trial drugs. And the net is that the overall response rate to this second or next therapy was about 50%, and the argument being made here is that these patients seemed to do better than you would have expected, or that one might have expected, and it raises the idea that having had checkpoint blockade therapy may either sensitize or change the disease, or the immune system, or something to make the next therapy work better.

So I think this is an interesting concept. Obviously it needs to be teased out, and can be confounded by a variety of other issues, but I think ultimately it's an interesting concept that a prior therapy could sensitize a subsequent therapy by perhaps priming or resetting in some fashion the immune system. Interesting hypothesis, needs to be proven more formally.

Next I wanted to mention an interesting study by Gilles Salles and colleagues, abstract 227, 'Single-Arm Phase II Study of MOR208 Combined with Lenalidomide in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma: L-Mind.'

This is a study looking at an FC enhanced humanized monoclonal antibody called MOR208, which targets CD-19, and the idea is that this antibody may lead to NK cell ADCC, macrophage mediated antibody dependent phagocytosis and direct effects. This study looked at this agent in combination with lenalidomide which has a number of different anti-lymphoma effects, and it's looking at patients with relapsed DLBCL.

So it's eighty-one patients with roughly a median of two prior lines of therapy, about half the patients had received two or more prior lines of therapy. Adverse events here included neutropenia and other cytopenias as well as asthenia. There were dose reductions needed to lenalidomide, which is fairly common, and the interesting part here is that the overall response rate was 58%. So in a group of patients with recurrent DLBCL, a combination of lenalidomide and an anti-body in patients who were ineligible according to the investigators for high-dose chemotherapy and auto transplant suggests that in this population with limited options, a 50% plus response rate was fairly notable, I think, and there are a substantial number of patients with ongoing responses, ongoing treatment, with a twelve-month overall survival rate of 73%.

So this combination will be looked at in more detail. Obviously there's no control group, it's a combination of two active drugs presumably, so knowing which component or combination being responsible, and having a control group would be of greater interest, but certainly this is an interesting response rate in patients with recurrent DLBCL.

And then finally the last bonus abstract that I wanted to touch on was abstract 451. This is from Shalin Kothari and colleagues from Roswell Park. It's a multi-center group looking at, 'Outcomes of Patients with Limited-Stage Large B-Cell Lymphoma with MYC Rearrangement with and without BCL2 and/or BCL6 Rearrangements: A Retrospective Analysis from 15 US Academic Centers.'

And so we have data that suggest and show I think fairly convincingly that patients with double-hit or single-hit lymphomas may have a less favorable outcome focusing on MYC rearrangements. In particular, there are retrospective data suggesting that these patients may be treated more- or should be treated more aggressively in retrospective comparisons of R-EPOCH, or more intensive regimens to R-CHOP. The suggestion stated in this group a more intensive approach such as R-EPOCH can be standard, and I would say that many centers around the country and the world use R-EPOCH or something more aggressive than R-CHOP as their standard approach here.

However, there has not been previously a lot of work on limited stage DLBCL with MYC rearrangements or disruptions, or the double-hit or triple-hit population. And so this was an analysis of patients that were fine to have stage one and two disease with either DLBCL or high grade B-Cell lymphoma morphology, and MYC rearranged features on cited genetics. The authors gathered 142 patients of which 105 fulfilled their inclusion criteria, and interestingly roughly half of patients received CHOP, roughly half of patients received involved field radiation, and then of the other regimens, EPOCH was used- or R dose-adjusted EPOCH was used as well as R-hyper-CVAD.

And the net was that the overall response rate was good, 90% or so, double-hit patients seemed to do a little bit less well in this group of patients. However, overall the two-year progression-free survival was 78% and the overall survival was 86%. For the entire cohort, fairly similar, perhaps slightly lower at 72% and 82% for the double-hit patients. And the net is that the choice of therapy did not seem to impact outcomes, meaning that patients had similar progression-free and overall survival whether or not they had RT or whether or not they had R-CHOP or a more intensive approach.

And so the net is that these are interesting data, it's a pretty large series, non-comparative data, but suggesting that limited stage MYC rearranged DLBCL patients, aggressive B-Cell lymphoma patients have a pretty favorable outcome, and not a clear benefit of a more intensive regimen, not a clear benefit of using radiation.

So again, perhaps some confounding issues in this study given that it was retrospective, but again suggesting that stage is an important factor in outcomes for this group of patients, and I think that's an encouraging piece of information.

So with that, we'll wrap up our summary of the 2018 Leonard List for the American Society of Hematology Meeting. I appreciate that you joined us today. If you'd like to follow me and our discussions on Twitter, you can track me down @JohnPLeonardMD. And otherwise we hope that you have enjoyed this episode of CancerCast, and you can take a look at all of our other episodes where we have covered a variety of different topics relating to cancer, supportive care, different malignancy screening, and issues around survivorship, as well as advocacy. And you can take a look at our portfolio of prior episodes. You can also subscribe to us. Download, subscribe, rate, and review CancerCast on Apple Podcasts, Google Play Music, or online at www.WeillCornell.org. We hope that you will continue to follow us. If you're just joining us for the first time on CancerCast, you can also write to us at cancercast@med.cornell.edu - that's cancercast@med.cornell.edu - with questions, comments, or topics you'd like to see us cover more in depth in the future.

That's all today for CancerCast: Conversations About New Developments in Medicine, Cancer Care, and Research. I'm Dr. John Leonard, thanks for tuning in.