ASH Review: Why FL Cells Don't Go Away (Maybe)

 Another ASH review. This one is is for anstract #553: "Longitudinal single-cell profiling of the bone marrow heterogeneity identifies the T-cell niche supporting cancer persister cells in follicular lymphoma."

This is the presentation mentioned by Dr. Jessica Okosun in the Follicular Lymphoma Foundation's video, which I posted a couple of weeks ago.  Dr. Okosun was excited about this because it potentially revealed some important new information about FL biology.

I'll be honest, I don't usually focus much on the biology-related research that I come across -- the kind of articles that tell us about biomarkers, and cells, and genes, and Tumor Microenvironments.  It's all incredibly important. But, honestly, it's also hard to read (there are usually strings of acronyms and initials that I get mixed up with one another), and it's also usually information that may lead to new research, that may eventually lead to clinical trials, but that may not show up for many years. It's much more fun to write about a stage 3 clinical trial that might have implications next month than to write about a protein or a gene that might not affect my treatment until 2038.

But, as I said, this kind of research is very important, since its the basis for the things that show up in the treatment room years from now. So I'll do my best to explain this one. But keep in mind that I'm not a cancer biologist. I will almost certainly oversimplify this.

The idea behind the research is the understanding that, since FL has a way of hiding (which is why so many of us are asymptomatic) and then of coming back after treatment, there must be something called FL cancer precursor/persister cells, or CPC. A persister cell is a cancer cell that is resistant to treatment in some way, so even if it seems like the disease has been successfully treated, those CPCs are hiding somewhere and then come out again later, and the disease relapses.

In Follicular Lymphoma, researchers already know that FL is hard to treat because of the Tumor Microenvironment (TME) -- not the cancer cells themselves, but a lot of the things that are happening around the cancer cells. For example, FL cells are infleunced by Treg (Regulator T Cells, a type of immune cell), activated Tfh (T-follicualr helper cells, another immune cell), and dysfunctional cytotoxic T cells (another immune cell that finds and kills damaged cells, including cancer cells).

(I could go more into these different types of T cells and what they do, but I don't think that's going to help explain anything. It will probably just confuse you and me.)  

However, as the abstract points out, with FL, researchers still haven't been able to identify the specific CPCs (those cancer cells that are hiding someplace) or the cells in the Tumor Microenvironment that might be helping the FL cells stay alive.

But they do know that the bone marrow might be a good place to look. \

So for this research, that's just what they did.  

The researchers took bone marrow samples from 19 patients who had been given Rituxan. They took a bone marrow sample at diagnosis, and another one 12 months after they had received Rituxan, so they could compare them. They also took bone marrow samples from 5 healthy donors so they culd compare results to them as well. 

What they found wasn't surprising. Remember that all of the Tumor Microenvironemnt examples were of T cells -- different types of immune cells that have some kind of influence on FL cells. They found that the "T-cell landscape" in the bone marrow was "highly heterogeneous" in the samples from FL patients. This isn't surprising to me because FL is a highly heterogeneous disease -- it acts differently in each one of us. They compared those to the "healthy" patients, whose T-cell landscapes were more uniform. 

More specifically,  they found that the samples from the FL patients had a "decrease of cytotoxic
CD8 T cells and naive CD4 T cells and an increase of IFN-responsive CD4 and CD8, Treg, Tfh-like, and
memory CD8 T cells." (I told you, it gets hard to read with all of the initials.) Those same cells that were increased are the ones that were associated with poor outcomes -- POD24 (where the disease returns within 24 months) and Time to Next Treatment less than 30 months. The things that decreased are the things that are associated with a better outcome -- longer Progression Free Survival and Time to Next Treatment.

There are more details about how some other parts of the Tumor Microenvironment and the differences they found, but I think you probably get the point. They seem to have identified some biomarkers that could show early on whether there will be good or bad outcomes, and these are potential targets for new treatments. 

And just to be clear about how they did this -- they took a sample of bone marrow and looked at it. Then they gave some Rituxan to get rid of B cells. And then they took another bone marrow sample to see what was left. And they found some important things -- a "preserved niche" in the bone marrow that could support survival of some (fairly rare) CPCs. It's not just cancer cells surviving treatment, it's also a bunch of immune cells that are protecting those cancer cells and allowing them to grow and persist. 

Is this the piece of the puzzle that we need to fix everything? It's impossible to tell at this point.

But I'm going to take Dr. Okosun's excitement about it as a very good sign. 

Still sifting through some more ASH commentaries to see if there are other things (besides Epcoritamab) that people are excited about. More soon, whether it's from ASH or someplace else.

 

ASH Review: Epcoritamab

If there was a Big Winner for Follicular Lymphoma at ASH this year, it was without a doubt Epcoritamab.

Epcoritamab is a bispecific antibody, meaning it has two mechanisms working. On one side, it attaches to a protein on the surface of the cancerous B cell, and then also attaches to a protein on a T cell, an immune cell. In this way a bispecific uses the body's immune system to treat the cancer.

The research that has everyone so excited is the results of a phase 3 clinical trial, also published in the prestigious medical journal The Lancet, as "Epcoritamab, lenalidomide, and rituximab versus lenalidomide and rituximab for relapsed or refractory follicular lymphoma (EPCORE FL-1): a global, open-label, randomised, phase 3 trial."

The results really are pretty exciting. This is a phase 3 randomized trial, which means the researchers split a large group of patients into two, so they could directly compare the results of two different  treatments. This kind of trial is considered the most accurate (rather than comparing one group to the results of a trial that happened a few years ago). In this case, one group was given R-squared (Rituxan + Lenalidomide/Revlimid), while the other was given R-Squared plus Epcoritamab. There were 448 patients in the trial (a pretty large number), and all had relapsed or refractory disease (they had already had treatment, and it didn't work or no longer worked).

With a median follow-up of 14.8 months, the Overall Response rate for the Epcoritamab group was 95% (versus 79% for the R-squared group). The Complete Response Rate was 83% for Epcoritamab and 50% for R-squared. 

The Progression-Free Survival for the Epcoritamab group was higher, with estimated PFS of 16 months in 85.5% of that group versus 40.2% in the R-squared group. (They had to use an estimate because some patients hadn't reached the median time yet.)

With a "triplet" -- a combination of three different treatments -- like this one, safety is always an issue. Three treatments might mean three times the effectiveness, but can also mean three times the side effects or adverse events. Grade 3 (serious) adverse events were higher for the Epcoritamab group (219 of 243, or 90% of that group, versus 161 of 238, or 68% of the R-squared group), which was to be expected. Cytokine Release Syndrome, which can be very dangerous, was low grade for the Epcoritamab group, and was managed by the doctors.

I was going to link to a few videos of Lymphoma experts talking about the results, but they're kind of all the same thing, with the expert repeating the numbers and talking about how exciting this could be (like this one from OncLive). And I do think it's exciting, having finally seen all of the data.

Any skepticism I have comes from whether or not patients will have access to it. It does seem to me that bispecifics are probably more accessible than CAR-T (the two are often talked about together, including by me). CAR-T is great, but more expensive (as one recent bit of research pointed out), which is going to make bispecifics a more popular choice for those who make those decisions about cost. But there are going to be still less expensive options for R/R patients, probably. I hope FL patients can get the best treatment available, no matter the cost.

This isn't the last we're going to hear about Epcoritamab. There were many ASH presentations on this treatment, for many different types of Lymphoma. Two that I thought were interesting were the results of a phase 2 trial of Epcoritamab and Rituxan for untreated FL patients (97% Complete Response Rate in a small trial), and Epcoritamab and R-squared in untreated FL patients (95% Overall Response Rate). 

But it's that randomized, phase 3 trial that really makes me think that Epcoritamab will be around for a while. A large number of patients over a long period of time. It seems pretty likely that it will be a regular part of treatment programs. It might take a while to get to that point, but it probably will.

I'm still looking at ASH abstracts and watching and reading commentaries. I'll have more soon. 

ASH Review from the Follicular Lymphoma Foundaton

The ASH meeting ended yesterday, so no more previews. Now we're into reviews. Over the next few weeks, there will be lots of Lymphoma experts writing articles and making videos that talk about what they found most exciting at ASH. They're helpful. They often provide more detail and analysis than I could get from the abstracts, and it's usually easy to see patterns when they all talk about the same thing.

For this first review, we'll look at a video sponsored by the Follicular Lymphoma Foundation. It features Dr. Jessica Okosun, a Lymphoma specialist and professor at Bart's Cancer Institute in London. (Prof. Okosun was one of the panelists for the FLF's webinar, "Charting Our Progress Toward a Cure" last summer.) 

You can watch Dr, Okosun's video here on YouTube, or go to the FLF's website and see it there with some additional commentary. 

The thing that excited Dr. Okosun the most was the research on Epcoritamab and R-Squared (Rituxan + Revlimid or Lenilidomide). If there was a standout for FL reseach at ASH this year, it was this one. Since it was presented a few days ago, I've seen about 20-30 articles about it, with phrases like "game changer" and "new standard." (I'm always a little skeptical about new treatments being talked about so excitedly. I'll get more into that at some point.) The results were also published in the prestigious medical journal The Lancet a couple of days ago, which is a bigger deal, since it means the data has been peer-reviewed by other experts. 

As Dr. Okosun says in the video, the research was a randomized trial with about 400 patients, half of them getting R-squared and the other half getting R-squared + Epcoritamab. The R-Squared group had a Progression Free Survival of about 11 months, with the Epcoritamab group had not reached its median after almost 15 months (meaning fewer than half of the patients had their Lymphoma return). 

She was excited about bispecifics in general -- there was additional research at ASH on Mosunetuzumab as well -- but she also pointed out some safety concerns. Bispecifics tend to increase the risk of infection in some patients, so as with any treatment, there needs to be some caution when giving it. 

Dr. Okosun was also excited about the research on the biology of FL that was presented at ASH. We still have some basic questions that we don't have answers to, like why FL comes back after it seems to have been treated successfully. She was excited especially about research by Dr. Karen Tarte, who presented data that looked at differences between FL cells at diagnosis and then at relapse. You can see that abstract here; I'll try to look at it and comment on it soon. 

As I said, there will be more commentary from Lymphoma experts in the next few weeks about what they found exciting at ASH. And I'm sure a lot of it will be about Epcoritamab. I have no doubt that it has the potential to make things better for Relapsed and Refractory FL patients. It will be a matter of getting it to them. 

More ASH reviews to come.  

 

ASH Preview: The Leonard List

This post is the next one in a series of previews for the ASH meeting, one of the largest gatherings of blood cancer specialists in the U.S. The abstracts (or summaries) of the presentations come out a few weeks before the meeting, so while they don't give all of the details of the research, they do give enough for me to see if it is interesting or significant enough to focus on and write about.

For this post, I'm going to do something I have done in the past -- look at The Leonard List. Every year, Dr. John P. Leonard, a Lymphoma specialist in New York, gives a list of what he thinks are the Top 10 abstracts related to Lymphoma at the year's ASH meeting. It's always interesting to see which of his Top 10 are focused on Follicular Lymphoma, and  which of them were on my list as well.

(And, to be clear, Dr. Leonard is one of top Lymphoma specialists in the world. I'm not saying my list is as accurate as his, in terms of significance of the abstracts. If it's important to you to know which research at ASH really matters, go with Dr. Leonard, not with me. I'm just a guy with a blog.)

These will be shorter discussions from me than the previous ASH posts, since we have several to talk about.

Number 10 on The Leonard List is abstract #52:  EZH2 and CREBBP mutation status identify a subset of patients who benefit from bendamustine- over CHOP/CVP-based immunochemotherapies in follicular lymphoma: Findings from the GALLIUM trial and validation in a large international cohort. This one was actually on my list of abstracts to review. It looks at data from the GALLIUM trial, which involved 1202 patients with Follicular Lymphoma who had not been treated yet. Half received Rituxan + chemotherapy (either Bendamustine, CHOP, or CVP) and the other half received Obinutuzumab + chemo (the same three possiblities). A few years ago, data from this trial showed that Bendamustine led to longer Progression-Free Survival than CHOP or CVP, but also showed that Bendamustine led to more high grade infections than the other two chemos. This led to the idea that Bendamustine might make CAR-T less effective if the CAR-T comes later, since the Bendamustine affects the T cells that CAR-T relies on. For this presentation, the researchers look at gene mutations in the data they collected to try to identify which patients might benefit from taking Bendamustine, and which might be better served with a different treatment. They found that mutations in EZH2 and CREBBP could help predict success with Bendamustine. Patients with CREBBP and wild-type EZH2 benefit most from Bendamustine, with much longer PFS and Overall Survival than other patients in the trial. The others had similar PFS no matter which chemo was given. Still some more research needed to confirm this, but it's they type of biomarker research that's been so difficult to find lately.

Number 8 on the Leonard List is abstract #5515 CD19 expression is preserved following CD19-directed monoclonal antibody therapy with tafasitamab. This is a fairly small study that focuses on one of the problems that comes with CAR-T. If you've been reading the blog for a while, you know that many FL treatments rely on targeting proteins on the surface of the cancer cell. Rituxan, for example, targets the CD20 protein, which is very common on B Lymphocytes (the white blood cell that turns cancerous in FL). Another common protein is CD19, and that's the one that CAR-T goes after. The problem is, for about 30% of CAR-T patients who relapse after CAR-T treatment, their B Lymphocytes no longer have the CD19 protein, which means a whole bunch of FL treatments won't work on them anymore (though there are plenty that will work since they don't work by targeting that protein). The research in this presentation looked at Tafasitamab, an anti-CD19 monoclonal antibody. The research looked at patients who had one of several B Cell cancers, including FL. They wanted to know if taking Tafasitamab had the same effect as CAR-T, resulting in losing the CD19 protein. They found that most patients did not lose the protein. The conclusion has to do with sequencing of treatments -- patients who are CD19-positive should receive a treatment like Tafasitamab first, and then CAR-T if necessary. It's a small study and a small piece of the puzzle, but for those of us with a cancer that often returns, that kind of planning is important. 

Number 4 on The Leonard List is abstract #5385  Evaluating the clinical outcomes of GLP-1 receptor agonists in untreated indolent non-Hodgkin's lymphomas undergoing active surveillance. I'll be honest -- I talked to my wife about this one and I wasn't sure I wanted to even write about it, for reasons you will see. But I'm going to follow The Leonard List here and add my commentary about it. This presentation looked at the possible effects of GLP-1 agonists (that is, medications like Ozempic, Wegovy, and Mounjaro) on watching and waiting. These are given to help control diabetes and, increasingly, for weight loss. The research looked at patients with indolent, slow-growing Lymphomas (including FL) who had been taking a GLP-1 before or after their cancer diagnosis, and who were able to watch and wait. In looking only at the whole group, they found that patients who had received GLP-1, about 17.3% required treatment during the study, versus 20.3% who had not taken a GLP-1. The patients in the GLP-1 group had a lower risk of acute cardiac events including myocardial or heart attack (4.9% vs 7.3%) and a lower risk of heart failure (10.6% vs 15.2% ). Looking only at FL patients, the results were similar, but also included analysis that showed that there was "a reduction in those who progressed to DLBCL" (which I assume means transformation) -- 4.5% vs 8.3%. The abstract does not say why the GLP-1s might contribute to these results, though in the introduction, they hint that it might be more about weight loss and controlling diabetes than about the medication acting on the cancer cells directly. Both contribute to inflammation and heart issues, so reducing them will reduce other problems.

So why am I reluctant to write about it? Well, I'm always extra careful when I write about something that that's kind of "in the news" and is also controversial, and I think both of things are true about GLP-1s. The one thing I absolutely do not want anyone to think is that taking a GLP-1 will somehow cure their FL. There's no evidence in this study that such a thing would happen. This study looks at a very particular population -- FL patients who are watching and waiting -- and makes conclusions about particular things -- increasing time to treatment, reducing heart issues, and possibly reducing transformation. Should you be taking a GLP-1? I have no idea. Talk to your oncologist about how much they know about whether or not it will have an influence on your cancer, and talk to your other doctors about whether it will have an effect on any other health issues you are experiencing. Your doctors are the best people to help you make those decisions. As I wrote above, I'm just a guy with a blog.

(I'm guessing this is going to be one of those ASH presentations that people talk about after all of the details are presented at the meeting. I'll share if I see anything with good analysis.) 

Finally, Number 2 on The Leonard List is abstract #117 "Lymphovision: A lymphoma-specialized foundation model for histology-based lymphoma classification and subtyping." I already wrote about this one. I guessed number 2 correctly! 

So that's The Leonard List for this year. In the past, Dr. Leonard has gone into a little bit further detail about his picks during a special podcast episode. However, that podcast was sponsored by his old institution, and he's switched jobs since last year. I haven't seen any notice on his Twitter/X feed that he's got a podcast episode coming up, but I'll keep looking. I'll post a link if there is one,

The ASH meeting starts very soon -- it runs from December 6 to 9. That means we'll start to see press releases, articles, and videos with more detail about some of the presentations. That means I might be moving soon from "ASH Preview" to "ASH Review," but I'll probably still be sharing some ASH content either way for a few more weeks. So stay tuned.

 

ASH Preview: Zevalin

As I said I my last post, when I do previews like this for the ASH meeting, I'm not trying to be comprehensive. If something seems important, I'll look at it. (You'll see a few of those coming up.) But if something seems interesting t me personally, I'll look at that, too.

This is one of those "interesting to me personally" previews. It's for session #1825 "Real-world outcomes of Y90-ibritumomab tiuxetan (Zevalin) in low-grade B-cell non-Hodgkin lymphoma: A single-institution experience."

Zevalin is a type of RadioImmunoTherapy, or RIT. You don't see much about RIT anymore, at least not in the U.S., and there's a reason for that. RIT treatments were created to solve a problem with blood cancers in using radiation. Radiation can be an effective treatment, particularly for cancers with solid tumors. A beam of radiation can be aimed directly at a tumor. But that's not the case with blood cancers -- the cells are always moving around in the bloodstream, so it is literally a moving target. RIT works by taking a monoclonal antibody (something like Rituxan), which targets a protein on a cancer cell (CD20 is the target for both Rituxan and Zevalin). It also includes a small bit of radiation. So when the RIT finds a CD20 target, it attaches itself to the cancer cell, putting the little bit of radiation onto the cancer cell and killing it. And even better, at least in theory, because the radiation is aimed at a very specific target, there is less chance of it affecting healthy cells, so there should be fewer severe side effects. 

Zevalin was approved by the FDA for Relapsed and Refractory Follicular Lymphoma in 2002, and another RIT called Bexxar was approved right around the same time. I was diagnosed in 2008, so there were lots of follow-up studies being conducted and reported on in those first few years after I was diagnosed. And it was all very exciting to me. I remember the first article from a medical journal that I really got excited about was a report of R-CHOP and Zevalin, where Zevalin was used a salvage therapy (that is, it was given after R-CHOP to kind of clean up any leftover cancer cells). The idea of using three different treatment types -- a monoclonal antibody, traditional chemotherapy, and an RIT -- that work on the cancer cells in different ways, just made so much sense to me. 

So Zevalin has been on my mind for almost as long as I have been an FL patient. And those early studies showed that it was very effective. I remember communicating with two or three folks who had been in trials for Zevalin, and who had been in remission for years.

So why do we hear so little about it now?

Well, at least in the U.S., it's for a couple of reasons, but the biggest was a ruling by the FDA about how Zevalin had to be administered. Because it involves some radiation, the FDA ruled that it could only be administered by a Radiation Oncologist, someone with about 400 hours of specialized training. So while Rituxan or CHOP can be administered right in the treatment room at an oncologist's office, they would need to send you to a specialist if they thought RIT was the best option. And even in 2008, there were already a number of other options for FL treatment, so there wasn't much reason to send a patient to another specialist, or to do 400 hours of specialized training themselves. 

Soon after that ruling, the maker of Bexxar pulled the treatment from the market.But Zevalin has stuck around.  I have no idea how often it is used these days, but as far as I know, it's still available. Interestingly, a few years ago, there was another attempt at getting an RIT approved. It was called Betalutin, and it was pulled after a phase 2 trial. I kind of predicted that was going to happen when I first started reading about it.  

So what is this particular ASH presentation about?

Well, it looks at "real world" outcomes for people who received Zevalin -- patients who were not in a clinical trial. Some of those folks were followed for 22 years, from the time Zevalin was approved by the FDA.

A total of 122 patients with B Cell Non-Hodgkin's Lymphoma (most of them had FL) from one cancer center were followed. 72 of them had received one previous treatment, 43 used it as a salvage therapy after chemo, and 6 used it as a first treatment. The median age was 64 years old. 

The Overall Response Rate was just under 78%, which is pretty great for an FL treatment -- 70.8% ORR for the R/R patients, 88.4% for the salvage patients, and 100% for the first treatment patients.

The media Overall Survival was just under 10 years for the whole group. (Remember, Overall Survival measures dying from any cause, not just something Lymphoma-related, and "median" means that half of the group lived less than the median number, but half lived more than the number.) The median OS was 6.5 years for the R/R group, 15.2 years for the salvage group, and 8.4 years for the first line group. The median time to next treatment was 7.4 years, and 18 patients developed a secondary cancer.  

In their conclusion, the researchers say that Zevalin still has a place in the treatment options for certain patients. That's probably true, especially considering it is about the same cost (maybe even a little cheaper) than something like Rituxan. But I also think it's very unlikely that it's going to suddenly get popular, given all of the other treatment options we have now.

It's always interesting to look back and think about what might have been. I certainly don't have any regrets about being treated with Rituxan instead of something else. But I also can't help but wonder what the path for other FL patients would have been if Zevalin had become more popular. It's not a perfect treatment, by any means, but it might have helped a lot more people than it was able to.

More ASH previews soon.

 

 

 

 

 

ASH Preview: LymphoVision

I'm finally getting around to looking at ASH abstracts.

For those of you who are new around here, ASH stands for the American Society for Hematology, the organization for doctors who specialize in blood disorders, including blood cancers. Every year in early December, they hold their annual meeting, and it's where some of the biggest news about Follicular Lymphoma gets shared. About a month or so before they meeting, they publish the abstracts -- the summaries of the research that will be presented at the meeting. If you're interested in reading on your own, you can find the abstracts here. You can enter a search term like "Follicular Lymphoma" or the name of a particular treatment, and you'll get the list of every abstract that deals with that thing.

Every year, I like to do a little ASH preview, and talk about some of the abstracts that I'm interested in. To be clear -- these aren't necessarily the most important abstracts (though I do try to guess what those will be, which is usually easy because of all the talk online about them). Usually it's just something that I find interesting. Like, this year, there's some research being presented about the long term success of Zevalin, an ImmunoRadioTherapy that I first wrote about in 2009. If you search for "Zevalin" in the blog, you'll see that I wrote about a whole bunch. But it never really gained acceptance as a treatment, for a specific reason. I'll write more about all of that soon when I do a preview of that ASH presentation. 

My point is, I usually write about things that interest me, not necessarily the things that experts find important. Some medical conferences end up featuring some groundbreaking research that really changes things for us as patients. But most of the time, it's the kind of small, incremental moves forward that are typical of cancer research. Science tends to move in inches (or centimeters) over many years, rather than in miles (or kilometers) all at once. 

At a meeting like ASH, that means lots of new research about treatments that are already in use, and maybe a few reports from phase 1 or phase 2 clinical trials that are very hopeful but still a long way from showing up in the treatment room. I read an article a couple of days ago where someone gave an ASH preview, looking at research for a whole bunch of blood cancers, not just FL. He says there is lots of research about "rival BTK degraders," as well as bispecifics and CAR-T treatments. Not necessarily big news about something new. But lots of Presentations showing that one company's version of a treatment might be a little better than someone else's. That's not a bad thing. Keep moving forward, inch by inch, centimeter by centimeter.

So all of that brings us to the first abstract that I want to talk about: "#117: Lymphovision: A lymphoma-specialized foundation model for histology-based lymphoma classification and subtyping."

I'll be honest -- I went through all of the abstracts and marked a bunch to look at more closely later on, and the only reason I marked this one was because the name "LymphoVision" made me laugh. It's definitely something that a hero from the Marvel Universe would have as a super power. Lympho Bob loves Lympho Anything. 

But it's actually a very cool presentation.

The research looks at Image Foundation Models, a type of huge AI-powered database. For cancer research, Image Foundation Models can be trained to look at tissue samples and determine if one is cancerous. They aren't used much with Lymphoma cells yet, but in research on other cancers, Foundation Models have actually been able to look at a sample that seems normal but that they accurately predict will mutate and become cancerous in the future. The researchers for this abstract have developed a Foundation Model that looks specifically as Lymphoma samples -- and they call it LymphoVision.

(They actually call it Lymphovision, without the upper case V, but I think it looks cooler that way.)  

For their research, they used 37 million tissue samples to train the program to recognize Lymphoma. They asked the program to perform several specific tasks, including finding FL in the sample and then classifying it as either grade 1-2 or grade 3. For that particular task, the program found 660 cases of FL -- 500 cases of grade 1-2 and 166 cases of grade 3, for an accuracy of 89.2%. When asked to identify a range of different types of Lymphoma, it had "high diagnostic accuracy" (you can see the results in the abstract). If you're wondering how all of that compares to humans, the abstract says "Based on historical
benchmarks from the 1997 International Lymphoma Study Group classification project, expert
hematopathologists achieved diagnostic agreement rates of 55% to 84%" using the same methods. 

The researchers know that more work on this is necessary, but they see a lot of promise in using tools like this for diagnosis in the future.

I don't know how much you all deal with Artificial Intelligence, but I think there is a general ambivalence about it -- one that I share. Research like this is wonderful, and shows how an AI program can save time and cut down on human error. But the technology is still in its very early stages and make lots of mistakes. That 89.2% accuracy still leaves 1 out of 10 patients getting an incorrect diagnosis. So it's not perfect. 

But I do agree that it holds some promise, and it will likely get better over time. (I'm in that weird space where I want some AI to improve quickly to make my health better, but other AI to improve slowly so I can hang on to my job for a few more years until I'm ready to retire.)

More ASH previews to come soon. 

 

 

Two Approvals and a Story

My email notifications have been very busy over the last few days, with news of treatment approvals in the US and in Europe. If I get that many notices, it must be a big deal. I'll tell you about them, but first, a story.

A couple of days ago, I went for my first CT scan in many years. It wasn't for cancer, but for a heart-related issue. (Everything is fine -- just needed to check on something to make sure it really is fine.)  I haven't had a cancer-related scan in a while because I haven't needed one, and my oncologist is pretty firm in his belief that if there isn't a reason to do a scan, we shouldn't do one. "Surveillance" scans, just looking to see if there are any problems, don't usually work that way. Something else happens that calls for a scan, and the scan confirms the problem. 

So that's what happened with my heart-related issue -- something else showed a problem that CT scan could confirm. It was different than any of my cancer-related scans. It was just a CT scan, not a PET scan, so there was no nasty liquid to drink, no IV with a contrast in my arm, no getting undressed. Just me on a table, gliding into a big donut. It took about 5 minutes. 

I've been so busy lately that I really hadn't had time to even think about getting this scan. So it wasn't until I was on the moving table that I even thought "Wow -- it's been a long time since I had a scan. I really don't like scans. There is way too big a chance that a scan is going to bring bad news." That little bit of scanxiety didn't kick in until I was in the middle of it.

And then the voice came on, the one that gives you instructions. So a male voice started speaking to me: "Take a deep breath....now let it all the way out.....take another breath.....now let it all the way out......Now breath in deeply and hold," but his voice went way up when he said "hold," like he was asking a question. Then he continued, "Now you may release your breath." This happened three times.

I almost messed up the scan because I started laughing a little.

The whole "hold" like it was a question was kind of funny. But then I started thinking about the last scan I had, several years ago, at my cancer center. The voice that spoke to me there had a British accent. So instead of saying "Now you may release your breath, " the British voice said "Carry on breathing."

"Carry on breathing" is not a phrase that we use in the US. I remember telling my kids about it, years ago, and them thinking it was very funny. 

So there I was in the CT machine, already smiling at the guy say "hold" like it was question, and now I'm also thinking about the British guy saying "Carry on breathing," and I know I'm about to laugh out loud and ruin this whole scan. 

Thankfully, I was able to hold in my laughter until I was done (thank goodness it was a short scan). But I did tell the technician about it, since she was looking at me funny when I was chuckling a little bit when she came back into the room. She thought it was amusing.

So it's nice to be in a place where I can laugh during a CT scan. I hope that's someplace we can all be someday, with no worries about anything. 

***************

Now, on to those approvals.

The first is from the US. The FDA approved Epcoritamab for two different situations involving Follicular Lymphoma.  

Epcoritamab is a bispecific, attaching itself to B cells with the CD20 protein, ans then to a T cell (an immune cell) with the CD3 protein. In this way, it brings the immune cell close to cancer cell, so the immune cell can take out the cancer cell. Epcoritamab was accelerated approved by the FDA for relapsed/refractory FL in 2024. Accelerated approval is kind of temporary, allowing the treatment to be used on patients while additional data is collected. So the first of the two new approvals is making the accelrated approval into a permanent approval. Epcoritamab can be given as a single agent for patients with Relapsed/Refractory FL who have had at least two treatments already.

The second approval is for Epcoritamab to be used with R-Squared -- Rituxan and Revlimid/Lenalidomode. R-Squared is being used more and more as a substitute for traditional chemotherapy, so just as there are combinations of chemo with new agents, there are also combinations with R-Squared. The potential problem with that kind of combination is that with three treatments, you have the potential for triple the side effects. In fact, safety was a concern when research on Epcoritamab was presented at the ASCO conference in 2024. But apparently there was enough data to lessen those concerns.

So we have a couple of more treatment possibilities in the US. (It has already been approved in Europe and Japan.)

The second approval is for Tafasitamab in Europe. This isn't a full approval just yet, but it's very close. This approval is the last step before it becomes official. It was recommended by the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP), which approved it for use with (again) R-Squared for Relapsed/Refractory FL who have had at least one other treatment. It needs to get its final approval from the European Commission.

Tafasitamab (also known as Monjuvi) is a monoclonal antibody, like Rituxan. But unlike Rituxan, which binds to the CD20 protein, Tafasitamab binds to the CD19 protein. So in theory, it should work well with R-Squared, since it works in a slightly different way. The same potential problems with safety can happen with this combination, but the clinical trial data seems to show that it was OK. Given how many notices I received about this, it seems like there won't be any major issues with it getting approval from the European Commission. 

I know that there is going to be some new data for Epcoritamab at ASH in a couple of weeks. I haven't looked to see if there will be anything new for Tafasitamab. I know I need to get moving on ASH previews. I hope to have some for you soon.

Dealing With Fear of Cancer Recurrence

The journal JAMA Network Open just published a study called "E-Health Intervention for Fear of Cancer Recurrence: A Randomized Clinical Trial." To me, the details matter less than the lesson that we should be reminded of.

The study looks at survivors of Colorectal Cancer, not a blood cancer. In this trial, 95 survivors were divided into two groups to measure their fear of their cancer returning (certainly something that we can all relate to, no matter which of our body parts was affected by cancer). All were given something called the Fear of Recurrence Inventory (Short Form). You can see the Inventory here -- it asks questions about how anxious one is about their cancer returning, using a scale of 0-4. With 9 questions of the form, the lowest possible score is a 0 (no fear at all), and the highest is 36. 

One group was given a specific intervention, the one that was being tested. It involved 6 modules that included written responses from a trained therapist, "delivered remotely, individually, and asynchronously over 10 weeks." In other words, the survivor didn't meet with a therapist, but was given personal written responses online to their fears and concerns. The other group was the control group. After taking the Inventory, they were given a diagnostic interview and then referred to a website with self-help exercises (no therapist gave them personal advice).

The trial found that the first group, who got the help from a therapist, had a much more successful time lowering their fear of recurrence. Between the two groups, there was a difference of about 19 points at the end of the trial (on that scale of 0 to 36). The score from the Inventory that signals a need for intervention is only a 3. By the end of the study, 81% of the first group has scores below 3, while only 43% of the second group did.

It seems like the trial showed that the specific intervention was very helpful for that group of Colorectal Cancer survivors.

But stepping back a little bit, I think it's a great reminder for all of us.

Sometimes we can deal with our own cancer-related mental health problems. And sometimes we need some help. 

In some ways, it's hard to compare Follicular Lymphoma patients/survivors with those who have had Colorectal Cancer -- or most cancers, really. Folks with other cancers have that whole "5 year" thing, where they can be told that they are likely cured after that time. That's harder for us. We have it drilled into our heads that our cancer is "incurable." I'm not sure what that means, and it's awfully hard to measure it with a cancer that is slow-growing and that typically gets diagnosed when folks are on the older side. But I think it's true for most of us that we understand that we'll likely live with this cancer for the rest of our lives, whether it comes back or not. (And remember I'm saying this as someone who was diagnosed almost 18 years ago and hasn't needed treatment in almost 16 years.)

There's a different type of mental burden for us, but it's a burden none the less. I know for me, personally, it has gotten easier over time to not think about it coming back. But it's always there, quietly lingering, and some days, it comes back loudly. But I've learned to live with it. 

My point is, there might be times when we can deal with the fear on our own. And there might be times when we need some help.

And it's OK to need some help. 

Even if it doesn't involve us directly, this study shows that there is lots of help available, and it can come in many forms. It might be, like in this study, getting written responses online from a professional. It might mean seeing a professional face-to-face. It might mean being part of a support group at our cancer center. It could mean being part of a support group online.  It could be something as simple as having coffee with a friend or loved one and talking.

I'm a big believer in talking about what we fear, and I think sometimes we need the reminder that it's OK to seek help when we need it. 

Where I live, the leaves are changing, the days are getting colder, and the songs about Santa Claus are starting to show up in stores. It's a joyous time for a lot of people. 

But it;s a stressful time for lots of people, too. A good time to start paying attention to how you're feeling and what you might need to do about it.

So this is just a reminder. If you need help, it's OK to ask for some.  

I hope everyone is doing well.  

50 Years of Lymphoma Lessons

I like to think I've learned a lot in my almost 18 years as a Lymphoma patient. Of course, I'm not an expert -- not like the actual doctors and researchers who have made Lymphoma their life's work. But I've read and written enough to know that there have been some major changes to the Lymphoma world since 2008.

But someone who has seen all of that and so much more is Dr. Bruce Cheson.

If you're a long-time reader of the blog, you might recognize his name. He is a now sort-of retired Lymphoma expert. I linked to him a lot because he wasn't just a well-known and influential researcher (he was responsible for introducing Bendamustine to the U.S.), but because he was very good at explaining things in a clear and often entertaining way. (I have a memory of him making a presentation at a conference somewhere with a glass of wine on the podium as he speaks.)

Dr. Cheson retired a few years ago, though he's still very active in many ways in the Lymphoma community.

A couple of weeks ago, he published something in the ASCO Post, the blog for the American Society for Clinical Oncology. The piece is called "My 50 Years in Lymphoma: Lessons Learned?" 

From the title, I expected a celebration of all of the progress we have made in 50 years in treating Lymphomas. But it's not quite that -- it's more of a list of the things that the research and treatment community still needs to make better.

He looks at different elements of the Lymphoma diagnosis and treatment spectrum -- classifying it, staging it, grading it, treating it, and deciding how successful the treatment was. For each, he gives a brief history (something a Cancer Nerd like me finds very interesting).

But he also points out how stuck we are in the past in many ways.

Take FLIPI for an example, which he discusses under "Prognotic Scoring Systems. I sometimes get emails or comments from readers asking me what FLIPI is, so I've seen how confusing it can be. FLIPI is the Follicular Lymphoma International Prognostic Index. Originally, FLIPI was used to categorize patients in clinical trials. The idea was that using a kind of "quiz" could help make sure everyone in the trial was basically the same, as far as their disease goes, so the can be more easily compared to one another. It doesn't make sense to see if a treatment worked on an asymptomatic stage 1/grade 1 patient who is 40 years old and then compare it to a 70 year old with stage 4/grade 3 bulky disease. So the FLIPI used categories like age, stage, and LDH levels to give a score from 1 to 5. A score of 0 is "low risk" and a score of 5 is "high risk."

One of the problems with FLIPI is that it is sometimes used by patients to guess their future. The link above will take you to a quiz that gives you a FLIPI score and prognosis. A score of 0 means you have a 70% survival rate for 10 years -- at least according to the quiz. A score of 5 means your 10 year survival is about 35%.

But the FLIPI is so general that it really tells you nothing about YOU as an individual. There are so many more factors that determine your situation than something like age. FLIPI is not a crystal ball. It cannot predict YOUR future. 

Back to Dr. Cheson. As he pints out, different versions of FLIPI have been prposed over the years, like FLIPI2 and FLIPI-m7, which looked at other biomarkers, but which really never caught on. (It was tried out on larger groups of patients and found that it didn't really hold up. Biomarkers have always been an issue for FL.) For Dr. Cheson, the problem is kind of the opposite of the one that I point out (which is that FLIPI probably makes your future look worse than it is). For him, the problem is that FLIPI doesn't accurately identify high-risk populations. It's that biomarker problem again. Being over 60 doesn't make you higher risk. It makes you average. 

He thinks most prognostic systems like FLIPI are decades old and do not reflect what we have learned about Lymphoma biology (despite the attempt at FLIPI-m7). They are useless in helping a clinical oncologist figure out the best way to treat a patient. And certain factors have changed with more effective treatments. Have three sites with swollen nodes instead of four sites doesn't change the recommended treatment. It's really not helpful -- not for patients who are worried about their futures, and not for the doctors who are trying to help them. 

Dr. Cheson points out lots of other things that are similar -- old habits that don't really apply any more. 

The question is, what to do about it? 

For Dr. Cheson, the answer is "a revolution": "To improve patient outcomes, a revolution is clearly needed for integrating staging, prognosis, treatment, and response assessment in the context of the remarkable proliferation of exciting new, nonchemo therapeutic agents for lymphoma." 

I hope the solution isn't quite as drastic as a revolution would suggest. But I can also see where someone like him, with a 50 year perspective, would think so. There is so much exciting news in the world of treatment that the basics of diagnosis and staging still haven't caught up with it. 

Here's hoping that revolutionary spirit spreads through the whole Lymphoma community.

Bispecifics vs CAR-T: The Difference in Cost

Good news: It's November, so the ASH abstracts are now available online.

For those who don't know or who need a reminder, ASH is the American Society for Hematology, and every year in early December, they hod their annual conference. It's the largest gathering of blood cancer specialists in the U.S., so there is usually some good research on Follicular Lymphoma that is presented. 

I haven't had a chance to look deeply into the abstracts yet, but I will soon. And as I usually do, I'll try to write about some the research that interests me and that I think will interest you, too. 

I've been so busy lately that I actually forgot that ASH was coming up soon. I got an email from Wendy, a very well-informed reader who reminded me that it was coming up.

And that reminded me to look at some of the links I have been collecting for the last month or so. I'm assuming there will be more research on bispecifics and CAR-T, the two treatments that, in my opinion, are the ones that get blood cancer specialists the most excited.  

One of those links that I saw very recently was about a presentation at the Academy of Managed Care Pharmacy (AMCP) Nexus, a gathering of pharmacists in managed care networks. Managed care refers to health care systems that aim to manage costs while not sacrificing quality. That's the aim, anyway. The important point is, the folks at this conference are as interested in how much a treatment costs as they are in how safe or effective it is.

The presentation that caught my eye is called "Total Cost of Care and Adverse Effects Assessment of Bispecific T-cell Engagers and Chimeric Antigen Receptor T-cell Therapies for Relapsed Refractory Follicular Lymphoma." The point of the research was the heart of what I said about managed care -- it wanted to look at how bispecifics compared to CAR-T, in effectiveness and safety, but also cost.

 I probably could have predicted the outcome of this. CAR-T is an exciting development in treatment, but it's also very expensive. The cost, when it was first approved, was about $500,000, give or take $100,000. That's a lot of money. I was in a meeting recently with some other FL patients, and one mentioned that she had been told that CAR-T, without health insurance, could cost as much as $2 million. (I don't know if that's true, but it certainly made me take notice.) 

In the research from this conference, the researcher looked at TCOC -- Total Cost of Care. That would help the high cost of CAR-T make sense. CAR-T is a personalized treatment, in which T cells are removed from a patient, changed in a lab, and then put back into the patient. That personalization is going to add to the cost. In addition, because of some potentially dangerous side effects, CAR-T patients are typically admitted to the hospital for as long as two weeks -- another factor adding to the cost. 

For some health care systems, that might make the treatment worth the cost, if it is so effective that the patient will never need another treatment again.

Ultimately, the study found that bispecifics might be a better choice for managed care. That is, they can be as effective, and as safe, but cost less. 

The Total Cost of Care for the CAR-T patients in the study averaged $702,000, while the bispecific patients' average total cost was $372,000. The total cost of the drug itself (as opposed to including hospitalization and other costs) was $521,000 for CAR-T, and $183,000 for bispecifics. 

The researchers also found the cost included having to deal with side effects. 52% of the CAR-T patients had significant side effects, adding about $9000 to the cost of care, while 23% of bispecific patients had side effects that added about $500 to the cost. 

(If you're not in the U.S. and all of these costs confuse you, try using a currency calculator. I'll post one here for your convenience, but there are plenty online.) 

I really hate thinking about treatment in terms of cost. I'd much rather write about the happy news that a brand new treatment had a 90% Complete Response Rate with manageable side effects. And that's what I usually write about.

But I know it's not the reality. I know many of us get certain treatments because if someone else is paying else is paying for them, they want to spend as little as they can. And that's true whether it's a private insurance company like in the U.S. or a public system like in Canada or the U.K. And I also know that sometimes I write about exciting new treatments that aren't even available in some countries -- at any cost -- because the cost is so high that it's not worth even making them available.

So it's probably good to know some of this insider information on how much things cost and how decisions get made.

One of the frustrating things about FL treatment is that there are no easy answers, no one clear path for treatment. It would be great if we could say the first line treatment should be X, and then if a second treatment is needed, it should be Y, etc. We don't have that certainty. There are lots of treatment options available that can do a good job.

But maybe there's some comfort in that, too. Maybe if we think a certain treatment that excites our oncologist would be the right one for us, but which a payer refuses to pay for, then we know there are other options. They will be less expensive, and maybe less effective, and maybe with a few more side effects. But we have options, anyway.

That's not necessarily the happiest way to think about it. But it's certainly realistic. And cancer makes us all realists.

I hope it's a long time before you need to make any tough choices. Take care.

  

Restoration

 Hello all. I want to let you know about a new piece that I have written that was just published in Intima: A Journal of Narrative Medicine.

It's called "Restoration," and I have to say, even with as much as I write, I'm more proud of this piece of writing than I have been of anything I have written in a long time.

I won't spoil it for you, but I can tell you that the "restoration" in the title refers to two things. The first is furniture restoration. It's a hobby of mine -- finding old wooden furniture that someone is throwing away, and  fixing it up, either to keep or to donate to someone else who might need it. "Restoration" of furniture is about trying to bring the furniture back to what it once was, before age and use made it something different.

"Restoration" also refers to our attempts to restore ourselves. As cancer patients and survivors, sometimes we wish that things could go back to the way they were, before diagnosis, before treatment, before everything else that comes with cancer. But furniture can never really be "restored." You can never bring it back to the way it was when it was created, as much as it might look like it used to be. And it's the same for us -- we can never really be the person we once were. And that's OK. Sometimes "renovation" is good enough for an old chair or side table -- making it something new, not making it was it was. And maybe we're the same way ourselves.

As I said, I was really happy with the way it turned out, because it was an idea that I had been turning over in my head for a long time, trying to make sense of it. I was finally able to say what I wanted to say, in the way I wanted to say it. I hope some folks find it valuable. Writing is good that way.

So if you'd like to read it, you can find it here. Thanks for clicking.

More Follicular Lymphoma stuff coming very soon. 

Take care.  

Music Therapy for Cancer Anxiety

My most recent email from CURE Today had an article on a recent clinical trial that looked at the benefits of music therapy on anxiety in cancer survivors.

The trial results were actually presented at the ASCO conference in the spring. The presentation was called "Music therapy versus cognitive behavioral therapy for anxiety in cancer survivors: A telehealth-based randomized clinical trial." In the trial, 300 survivors of different types of cancer were split into two groups. All of them had reported anxiety for at least one month. (It probably was not hard to find cancer survivors with some anxiety.) The people in the first group were given Cognitive Behavioral Therapy. (You can read more about CBT here; in the trial, it was considered the standard of care -- the treatment that most people would get if they had anxiety.) The folks in this group met with the therapist once per week for seven weeks by Zoom or other telehealth system.

The other group had music therapy once a week for seven weeks. A separate description of the trial said this consisted of "custom treatments" created by a music therapist "that may involve listening to music, singing or writing a song."

The results showed that the music therapy was non-inferior to the CBT. In other words, the folks in each group experienced about the same reduction in anxiety. The goal of the trial was to show non-inferiority, not superiority. In other words, the researchers wanted to show that both options were useful, rather than showing one was better than the other. CBT works, but some survivors can't do, or don't like it, so having another options -- especially one that is convenient because it can be delivered virtually -- is important. 

One of the big conclusions of the study is that Music Therapy has a long-term benefit. Listening to music, or singing, or writing a song can have a short-term effect that we've probably all experienced.  Your favorite song comes on (Maybe Lizzo's "Good As Hell," to give a completely random example), and it makes you feel good to hear it or sing it or dance to it. But doing it consistently, or time, can have positive effects on anxiety as well.

 I write about music here occasionally. I'm one of those people who remember song lyrics. I'm getting to an age where I forget why I walked into a room and have to turn back around and try to trace my steps and thoughts to remember. But I can sing all the words to the theme song from the TV show "Hello Larry" from when I was 12. So I have millions of words stored somewhere in my brain that show up at times without my asking. Some songs kind of haunt me. They have innocent lyrics that make me think about difficult things. And some that are just fun and make me happy. And some that are really sad, and I like them too, because they can make me sad for just a few minutes and kind of get it out of my system. (Aristotle figured all of that out about 2300 years ago.)

All of this got me thinking about conversations I've had with other cancer patients and survivors who have told me about their favorite Cancer Songs, the ones that they listen to to when they need that short-term boost. Many of them of meant to be inspirational. Some seem to have no connection to the idea of trying to pick yourself up. And a bunch of them, I confess, are songs that I don't like at all, and if I had to hear them every morning to inspire me to face the day, I'd probably stay in bed. What inspired one of us doesn't inspire all of us -- and doesn't need to.

I'm going to share the Cancer Song that I enjoy most.  I've shared it here before. It's called "Swim" by a band callad Jack's Mannequin. Their lead singer and songwriter, Andrew McMahon, is a survivor of Acute Lymphoblastic Leukemia. The song is about trying to stay afloat when things are difficult. You can read the lyrics here -- it's pretty easy to believe it was written by someone who had been given a cancer diagnosis.

So here's my question for you -- what's your Cancer Song? What music inspires you when you're having one of those tough days? Share in the comments. I'm always looking for new inspiration.

And this research is a good reminder that you don't have to struggle alone when things seem overwhelming. The trial is about survivors, but remember that anyone who has been diagnosed, and is still alive, is a survivor.  If you're having a bad day, and putting on some music makes you feel better, that's fantastic. But if things seem overwhelming, and Taylor Swift isn't helping, it's OK to find help. The study is about people working with trained therapists, not about people trying to do it alone. 

Take care of yourself.

 

FDA Fast Track Designation for EO2463

Last week, the FDA grated Fast Track designation for a new immunotherapy treatment called EO2463. (It will probably get a cooler name soon.)

Some reminders before we go any further: Fast Track designation means that a proposed treatment has the potential to do something new, and so it gets extra help from the FDA to help it through the approval process. Its a way of trying to get treatment to a group that has great need for treatment. In this case, that group is Follicular Lymphoma patients. (The news article about this is not clear about the specific population of FL patients, though the National Cancer Institute page for the clinical trial specifies relapsed/refractory patients with FL and some other indolent blood cancers.)

 Immunotherapy is a group of treatments (like chemotherapy is a group of treatments) that uses the body's immune system to work against the cancer. Our immune systems are usually good at fighting off invaders, like bacteria or viruses). But cancer cells aren't invaders -- they are our own cells, but they refuse to die like they are supposed to. So immunotherapy treatments usually work by either changing our immune cells to find and fight the cancer c ells, or changing the cancer cells so they can be recognized by our immune system as invaders.

EO2463 is a very interesting treatment that takes a unique approach to identifying tumor cells. It's a little complicated, so I've tried to do a bunch of reading and watching to help me understand it. (This video helped.)

The company that makes the treatment focuses on bacteria in our guts. Gut bacteria is kind of big news these days, as researchers are looking into all kinds of ways that our gut biome affects our health. (Though not all of those claims have solid evidence.)

The role of gut bacteria in this treatment is different. The company uses Artificial Intelligence to identify over 20 million different proteins that exist in the gut. Their AI program can help identify proteins that are very similar to those that exist in the body, especially proteins that exist on certain cancer cells.

That distinction between the gut bacteria proteins and the human proteins is important. The bacteria in our gut play important roles, but they aren't meant to leave the gut. If they do leave it, our immune system takes over. Immune cells are meant to recognize and fight off invaders (like bacteria or viruses). When they encounter one, they eliminate it and then remember it, so if they encounter it again, they can eliminate it very quickly. Gut bacteria are included on that list of invaders. As long as they stay in the gut, they are welcome to hang around, and the immune system leaves them alone.

So we have two things happening here. First, you have gut bacteria that are considered invaders if they leave the gut. Second, you have proteins from the bacteria that are very similar to proteins on cancer cells, like the CD20 protein that is on the surface of Follicular Lymphoma B cells. 

When you put those two things together, you can develop a cancer treatment. Create a treatment that targets CD20 (and some other proteins) but create it in such a way that it tells immune cells that the cancer cell is really a bacteria that escaped from the gut and needs to be eliminated. Because the treatment is engaging an immune cell called a Memory T Cell, which remembers invaders, the thinking is that the treatment will be long-lasting.

[A note to you language nerds: I know that "bacteria" is the plural form of "bacterium," but I'm calling a single one a "bacteria" anyway because I think it sounds better. Shakespeare made up words, too, and it's my blog, so I do what I want.] 

The Fast Track designation was earned by the results of the SIDNEY clinical trial. This is a phase 2 trial involving 60 patients split into 4 cohorts. As I said above, there are several different blood cancers being targeted in the trial. Patients are given EO2463 on its own and in combination with R-Squared or one of its components, Rituxan or Lenalidomide/Revlimid. 

The early results are promising. The first 13 patients have an Overall Response rate of 46%, with no severe side effects. The makers of the treatment see this as a possible alternative to watching and waiting (though it's not clear if they are targeting untreated patients.)

I have to say, I'm kind of fascinated by the approach, using AI to identify possible targets based on gut bacteria. But there are also lots of questions to be answered -- as is always the case with a phase 2 study. My guess is that there will be more information at the ASH conference, which is happening in less than 2 months. 

But Fast Track is no guarantee of success. This is definitely one that I will keep an eye on.

 

Stem Cell Transplant vs CAR-T, with a Cannoli

If you read the title of this post and are now very confused, I'll explain below. 

But before I get to that, I want to remind everyone to take the Follicular Lymphoma Foundation's annual survey. The survey will be available until October 19, so you only have a few more days from when I am posting this. It's a chance to have your voice heard - the FLF shares results with oncology researchers and clinicians, so together, we can help them understand the things that think are important for them to know about patients. 

The survey is anonymous and shouldn't take more than 10 minutes to complete. Thanks for your help with this.

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Now, about the title of this post:

CancerNetwork is the web site for the medical journal Oncology, and they sponsor a series of recorded debates called CancerNetwork Face-Offs. In these events, cancer experts are divided into two teams. Each team takes one side of a particular controversy in oncology, and makes a presentation about it. The idea is make these events educational, but also "fun" -- as much fun as anyone can have in discussing cancer.

(To be clear, I am all for fun, even in discussing cancer. It's obviously a serious business, but I can appreciate that people who are around cancer patients all day might want to add a little levity to their jobs.)

Part of the fun is in coming up with team names. So, for instance, in one Face-Off, two teams of oncologists from Chicago debate about....well, let me just copy the description at the start of the web page: "Panelists discuss various aspects of lower-risk myelodysplastic syndromes, including trial results on erythropoiesis-stimulating agent timing and novel agents like luspatercept and imetelstat, treatment sequencing and timing debates, personalized approaches based on erythropoietin levels, and complex case management balancing immediate symptom relief with long-term strategies."

The fun part? One team is named after the Chicago Cubs, and the other after the Chicago White Sox, the city's two Major League Baseball teams.  

Now, back once again to the bog post title. Some of these Face-Offs include videos of the debates. But their most recent one included a transcript of the event, with the title "Boston’s Best Did Not 'Leave the Cannoli' in Battle of Lymphoma Top Trials."

This one caught my eye for three reasons. First, it was about Follicualr Lymphoma, at least partially. Second, the oncologists on the panels were all from Dana-Farber Cancer Institute in Boston (the city where I was born and raised). And finally, the teams were named after two well-known pastry shops in Boston, Modern and Mike's. So the "leave the cannoli" is related to the pastry shops, but also is a reference to a famous lime from the movie The Godfather.  It's one of my favorite films. So how could I not write about this?

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That's a long introduction to a post, I know. I suppose you want some details of the actual face-off.

The two teams debated whether or not CAR-T was "better"than Autologous Stem Cell Transplant. It isn't really about these two treatments going head-to-head, but rather about the two teams doing their best to present information in a way that is both fun and informative.

The teams discuss the results of some recent clinical trial updates, look at case studies of patients, and then whether ASCT or CAR-T is better.

First of all, I'm not sure this is a fair fight. The last time I wrote about Stem Cell Transplants in any serious way was almost 10 years ago, and even then, the subject was about whether or not they were still a good option.  And there has been so much progress in FL treatments since then, it's hard to imagine anyone could make a strong case for Auto SCT over CAR-T.

If you're fairly new to all of this, and don't know what a Stem Cell Transplant is, here's a quick description: Patients who receive a Stem Cell Transplant receive very aggressive chemotherapy, aggressive enough that it pretty much destroys their immune system. It can take up to 30 days for the body to recover that system. But that leaves the patients vulnerable to all kinds of problems, since they have no defense against even the weakest virus. So they are given a Stem Cell Transplant, putting immature immune cells into their bodies that can grow into immune cells quickly -- maybe within 7 days -- leaving them much less vulnerable.

There are two types of Stem Cell Transplants. An Autologous STC uses the patients own stem cells. Tey are removed from the body before the patient receives chemo and then put back in after the treatment. An Allogeneic SCT uses immune cells from a donor that are a match. The danger with an Allo STC is that the patient's body can reject someone else's cells. The danger with the Auto STC is that those removed cells might have some cancer in them. Auto STC is considered less aggressive, but Allo STC usually had a greater chance of a cure, when it was successful.

(A Bone Marrow Transplant is very similar to a Stem Cell Transplant. The same dangers apply.) 

You can see how an Auto STC could be compared to CAR-T. They both involve removing immune cells and then putting them back in later. But the CAR-T cells are changed in ways that help them to locate cancer cells and remove them them. The Auto STC cells are just going back to their job of being immune cells - they aren't necessarily targeting cancer cells.

It's an interesting debate overall, even if the Auto STC folks had the harder job.  

And to be clear, Stem Cell Transplants are still used. There's no definitive answer when it comes to Lymphoma treatment. Every patient's needs (including their financial situation) has to play a part in the individual decisions about treatment. CAR-T is great, but it's not the best choice for everyone.

Cancer Nerds will enjoy reading this transcript. And whether or not this is your idea of "fun," it is always interesting to me to see experts delve deeply into a topic, present some interesting data, show how it applies to real people, and help us stay informed.

 

Mental Health Awareness Day

Today is World Mental Health Day. 

I found out about it because a notice popped up on my computer. The notice featured a green ribbon, which is the color for mental health awareness.

Of course, Lymphoma awareness uses a lime green ribbon. But the mental health ribbon looked kind of lime-like on my computer, so I had to look it up and make sure we weren't sharing the same ribbon color. These things are important. (Not really.) 

But when I saw that the two ribbons might be the same color, it seemed very appropriate to me, particularly for Follicular Lymphoma. As I have said for a long time, for many FL patients, the symptoms and side effects of the disease are not physical, but emotional, mental, and spiritual. Lots of us were asymptomatic at diagnosis, and maybe stayed that way for a long time. For me, it was two years of watching and waiting.

But even with no or few physical symptoms, there are plenty of mental ones during that watch and wait period.  (The Follicular Lymphoma Foundation just did a webinar on Watching and Waiting, and of course, issues related to mental health were a major part of of the discussion.) 

And there are plenty of other times during our lives as FL patients when mental health issues are important. Certainly at diagnosis. It's such a surprise for many of us, especially when we're asymptomatic. I've spoken with so many FL patients who say they were in the best shape of their lives when they were diagnosed -- again, myself included. That shock takes some time and effort to deal with. Even those of us who suspected that there was an issue still have the shock of having it conformed. "You have cancer" might be the scariest words in the world, despite all of the advances in cancer research in the last 20 years. 

And then comes treatment, and all of the mental health issues that come with it. Uncertainty over whether it will work, or whether there might have been a better choice. Fear of physical side effects -- still a huge concern for so many patients. And the mental health issues that come with being physically weakened by treatment, and having to worry about finances and every day life.

And then, post-treatment. the fear of recurrence. Even that one is different for us as FL patients. We've been told since diagnosis that the disease is incurable, and chances are good that it will return even after successful treatment. Dealing with that possible return has its own special mental health challenges.

And then, there's the mental health challenge that I think doesn't get talked about enough -- guilt. There's the survivor's guilt of going through treatment. There's the guilt that comes from being in an online group and realizing that others have had it much rougher than you have, and wondering if yu have anything to tell them that's helpful.

I'm not listing all of these mental health challenges because it's in any way fun. 

I'm listing them because I've been through each of them myself.I think there is something very special about reading or hearing about someone else's problems and realizing that you are not alone in having that problem. If, for example, you feel some kind of guilt related to your FL, know that you're not the only one. There's some comfort in that.

Which is ultimately what "awareness" days are about. They're about a collective understanding of something, and hopefully, a collective resolve to do something about it.

The FL Community Podcast's most recent episode is on mental health issues. It's worth listening to; you'll get an even greater sense that you're not alone in feeling what you're feeling.

And remember that if having Follicular Lymphoma gets a little overwhelming sometimes, that's OK. There are places online to have conversations with other FL patients and to get some reassurance. (And I'm always happy to listen, and to offer advice if I'm asked for it. I respond to every email that I receive.) And if talking it through isn't working, talk to your oncologist's office for advice on mental health professionals that might be affiliated with your cancer center. It's ok to seek professional help if that's what you need. 

I hope everyone has a great day today. Do something nice for yourself. 

 

Acalabrutinib + R-Squared for FL

The journal Nature Communications published an article a couple of months ago (I know, I'm behind on things) called "Frontline acalabrutinib, lenalidomide and rituximab for advanced stage follicular lymphoma with high tumor burden: phase II trial." 

It's a follow-up on some research that was presented at the ASH conference in 2023.  

In this study, researchers added Alcalabrutinib (also known as Calquence) to R-Squared. Alcalabrutinib is a BTK inhibitor. Just like other inhibitors, its job is to inhibit, or stop, something from happening -- in this case, Bruton's Tyrosine Kinase, an enzyme that is necessary for B cells to develop. B cells are, of course, the type of immune cell that includes the cells that can lead to Follicular Lymphoma. And that's what happens with a BTK inhibitor. The BTK enzyme does its job too well and won't die off, meaning the B cell won't die, leading to cancer. A BTK inhibitor stops that process and lets the cell die the way it is supposed to. 

Alcalabrutinib is already approved for some other blood cancers -- Chronic Lymphocytic Leukemia (CLL), Mantle Cell Lymphoma (MCL), and Waldenström's macroglobulinaemia.  So it makes sense that researchers are trying it with FL. However, there have also been several other BTK inhibitors that are effective with other blood cancers, but not FL.

The presentation at ASH in 2023 showed that this combination of Alcalabrutinib was very promising. The research is from a phase 2 clinical trial with 24 patients (a pretty small number). The patients had not received any treatment yet. The Overall Response Rate was 100%, and the Complete Response was 92%. After 26 months, 6 patients had their disease progress. The most common serious side effects (grade 3-4) were low neutraphils, a type of white blood cell, 58%, liver function test elevation (17%), infection (12.5%; 2 out of 3 related to COVID19), anemia (8%) and skin rash (8%). 

The Nature article was meant as a follow-up, looking at some longer-term data. The researchers were especially interested in what they call CR30 -- how many patients were able to maintain their Complete Response after 30 months. For them the CR30 rate was 65%. I'm not sure how that compares to some other treatments, but it seems positive. (This is a single-arm study, meaning they didn't split the patients into two groups so they could compare two treatments directly).   

After a median follow-up of 43 months, the median PFS (Progression-Free  Survival) was not reached, meaning more than half of the patients had not progressed. The PFS rate after 2 years was 79%, and for 3 years it was 62%. The POD24 rate was 17%, meaning 17% of patients who had a response had their disease return within 24 months. About 20% of FL patients are POD24, so this seems roughly in line with that number. 

Overall, the numbers look very promising. It will be interesting to see how this goes in a larger phase 3 trial.

I think what's really interesting, though, is the number of articles I've seen recently that look at R-squared triplets -- combinations if Rituxan, Revlimid (Lenalidomide), and something else. It makes sense. R-Squared has been shown to be as effective as traditional chemotherapy, but with a different set of side effects. SO instead of combining a single agent with chemo, researchers are hoping a combination with R-squared will increase effectiveness, hopefully without increasing side effects. That seems to be the case with this triplet, making a BTK inhibitor more effective than it has been on its own.

 Time will tell. 

Take This Survey about Follicular Lymphoma!

The Follicular Lymphoma Foundation is conducting its annual global patient survey, and I strongly encourage you to take a few minutes to respond.

The survey is anonymous, and takes about 5-10 minutes to complete.

The FLF conducts a survey every year to get input from FL patients from around the world about their experiences. They share the results on their website for patients to look at, but they also share the results with oncologists and other medical professions at medical conferences. A few months ago, they shared results from one of their surveys at ASCO, one of the largest gatherings of oncologists in the world. By telling oncologists about how patients and caregivers prioritize treatment decisions, they were able to show that doctors and patients think differently. It's a great way to have the voice of patients heard, and potentially change the way oncologists do their jobs. 

This survey asks questions about experiences with treatment, and about the kinds of emotional issues that FL patients have to deal with. It's very valuable information -- the kinds of information that don't usually show up on surveys.

(Which reminds me -- the latest edition of The FL Community Podcast is out now, and it's on "Mental Health and FL: Coping with the Psychological Impact of Cancer." I haven't had  chance to watch/listen yet, but I'm guessing Dr. Paul, one of the hosts, will have lots of good things to say, since he's a mental health professional, and Nicky and Nicola have had plenty of experiences to share as well.)

You can click here to find out a little more about the survey and click on the link to begin.

A couple of things to help you get oriented (I already took the survey, so I know these things):

You can take it in English or Spanish.

Some questions ask you to choose one item, and when you choose it, it will automatically move to the next question. 

If you need to go back and change an answer, there are two small arrow in the lower right corner that will let you do that. Don't feel like you can't go back and forth just because the survey moved forward on its own. 

I hope you will take a few minutes and complete the survey before it closes on October 19. A large response will benefit all of us.

 

 

Biomarkers in Stage 1 and 2 FL (plus, a chance to party!)

Interesting research this week from the International Journal of Molecular Sciences. An article describes research that may have found some biomarkers in patients with Stage 1 and 2 Follicular Lymphoma.

A little background. More than half of FL patients are diagnosed with stage 3 or 4 disease. Stage 1 and 2 certainly happen, but less often than advanced disease. Stage 1 in particular is located in on place, meaning it is easier to treat with traditional radiation. Some FL patients who receive radiation don't need further treatment, and some will eventually relapse.

The article is called "Proteomic Profiling of Limited-Stage Follicular Lymphoma Reveals Differentially Expressed Proteins Linked to Disease Progression Post-Radiation Therapy." It looks at a fairly small number of patients -- just 26 -- with stage 1 or stage 2 FL, who were treated with radiation. Nine of those patients experienced progression of disease, while the other 17 did not. With two groups to compare, the researchers used "high-throughput mass spectrometry-based proteomics" to examine biopsies from the 26 patients. Basiclaly, this is a method that helps researchers separate out and identify the different substances in a sample like a biopsy.

The process found a total of 1940 different proteins in the biopsy samples, with 78 of them showing up differently in the two groups. Researchers already know what function many of these proteins serve in the body. They may be part of the path of proteins and enzymes and genes that make a cell grow and keep it from dying when it is supposed to, resulting in cancer. Perhaps not surprisingly, the researchers found that proteins that do these things were not as present in the samples from the patients whose disease did not progress.

They found two particular proteins, CASP4 and CASP8, that seemed to correlate with shorter Progression-Free Survival. They point to other research that found the same proteins in advanced stage (stage 3 and 4) FL patients. 

They hope that further research will show that CASP4 and CASP8 are reliable biomarkers for predicting disease progression in FL. That will take some time to test out, but it would allow doctors to potentially recommend more effective treatments to individual patients.

This is a small study (26 patients) involving a limited population (FL patients with stage 1 or 2 disease that have received radiation), but it has larger implications. It's another attempt to identify biomarkers to help guide doctors and predict how a disease might behave. Identifying biomarkers seems to be more and more of a priority for the Lymphoma community lately -- they were brought up by Dr. Smith in the FLF's midyear report, and are important to the identification of potential FL subtypes, to give a couple of recent examples. It might not be that the community is paying more attention to it. It could be that there has been more success lately, and that's why we're seeing more about it.

Whatever the case, it's a cause for hope. 

******************

I want to make a quick mention of a Follicular Lymphoma-related event happening in November.

I know many of you are part of the Living with Follicular Lymphoma group on Facebook. It's a good group to be a part of, and I check in every day. It has almost 15,000 members from around the world. 

On November 11, they will be celebrating their 10th anniversary with a big party in London, sponsored by the Follicular Lymphoma Foundation. And everyone is invited. 

There is currently a poll being conducted in the Facebook group asking if people might be able to attend. If you are in the UK or nearby, or are just looking for an excuse to go to London, join the group and let them know so they have an idea of how big a party this will be.

Unfortunately, I cannot make it -- a tough time of year for me to travel. But if it had been at another time, I would have bought my plane ticket.

I can't tell you how incredibly valuable this experience is going to be for the people who are able to go. It is so very rare that we get to meet with people who have had the same experience with FL as we have had. There is something so uplifting about talking to someone who can smile and say "I know exactly how you feel!" and you know that they really do. If it's at all possible for you to be there in London, then try to be there. It will be a life-changing experience for you.

 Take care, everyone.

 

 

FLF's Midyear Research Update

The Follicular Lymphoma Foundation just published their mid-year update on Follicular Lymphoma Research. It's a fairly short document, and fairly easy to read (it's written by Dr. Mitchell Smith, the FLF's Chief Medical Officer, who always does a  good job of explaining things well).

Most importantly, it's very hopeful, pointing out the progress that's being made in FL research. 

I want to point out a few things that I found interesting, though I encourage you to read the report yourself.

First, I liked this line near the beginning: referring to the name of their symposium at the ICML conference in Switzerland this year, "Charting Our Progress Towards a Cure in FL," Dr. Smith says the title "reflects how the research community is increasingly convinced that FL will be curable -- the question is how and in what time frame."

That's a very hopeful thing to say!

I personally don't like to talk about cures for FL, because I've been dealing with it for over 17 years and I don't like to get my hopes up. The whole idea of a cure is complicated, given how hard it can be to measure a cure. But I do believe it will be considered curable one day, as the FLF report says, and it's very encouraging to hear that the Lymphoma community is feeling that same way. 

The report looks at three different types of research: from clinical trials that test out treatments; from translational developments that looks at biomarkers that might predict how a patient will react to treatment; and from biological research that identifies new information about how cancer cells stay alive and grow, which may open up new targets for treatments.

The clinical trials that Dr. Smith mentions are things like CAR-T and bispecifics. CAR-T is "maturing," meaning it's been around for a while so we're getting more information about how it works long-term. For example, about 50% of patients who were given one type of CAR-T remained progression free after 4 years, including about 45% who were POD24. That's great. I remember early research that had about 33% of CAR-T patients having a long-lasting response. It's improving.

Dr. Smith also points out that bispecifics don't have as much long-term data to look at, but what is there is encouraging, especially when they are combined with R-Squared. In general, there are more and more attempts at chemotherapy-free combinations, and more success with them.

One very interesting thing that he mentioned was the approval of Tafasitamab combined with R-Squared. The effectiveness is greater than most treatments currently available. However, he says, it might not be used quite as much as it could be because it requires "frequent hospital visits" and could be less effective than newer bispecifics like Epcotamab + R-squared. (As you may know, I've been thinking lately about how often Tafasitamab will be used and what might complicate that use.)

The clinical trial results are always the most interesting, because they are the easiest to understand and also the research that is closest to showing up in the doctor's office. But the more biology-based research is just as important, because they are the first steps in that clinical trial research. He mentions the research that has proposed three different subtypes of FL as well as research on the Tumor Microenvironment in FL (the stuff that surrounds the cancer cells, not just the cells themselves). 

He ends with another very hopeful quote about the state of FL research and the search for a cure:

 "It is clear the FL research community is moving from cautious optimism to genune confidence that cure is an attainable goal. By uniting scientific innovation, collaborative trials, and patient advocacy, we can accelerate the shift from managing FL as a chronic disease to eliminating it altogether. We are advancing faster than ever -- and with ongoing collaboration, the horizen for those living with FL grows ever more hopeful." 

Some excellent words to hang on to.

I encourage you to read the full report. You can find it here.

Stay hopeful, everyone.