Peace

I want to wish a Merry Christmas to all of you who celebrate. 

And whether or not you celebrate, I want to wish you Peace. 

"Peace on Earth" is a phrase that is often associated with Christmas. It was part of the message that angels gave to shepherds in announcing the birth of Jesus. It's the one I always gravitate to at this time of year.

I've given this same message on Christmas many times to you all, and it feels like I'm just repeating myself. As much as I want there to be peace on earth every year, it seems like there is less of it. Even Pope Leo a couple of days ago asked the world for just 24 hours of peace. 

And it's not just conflicts between nations, but within nations, too. Where I live, there is so much division, so many people who won't even talk to one another because of what they see as their differences. They can't see that they have so much more in common. That turmoil in the world makes it hard to feel good inside -- to have some inner peace. 

And inner peace is what I wish for us all. 

I'm coming up soon on my 18th diagnosiversary. You'll read more about that in a few weeks.  In many ways, life as a Follicular Lymphoma patient gets easier with time. You come to believe that you really can live a "normal" life with this disease -- whatever "normal" means.

At the same time, 18 years as an FL patient means 18 years of an aging body. I was a young, healthy man when I was diagnosed at 40 years old.  I was running in 5k and 10k races, starting to train for a short triathlon, enjoying time with my young kids, and telling myself that 40 wasn't so bad. Now I'm closing in on 60, juggling three different Electronic Medical Records portals, arranging pill bottles so I don't take the wrong ones at the wrong time, and going to physical therapy twice a week for a knee problem that came out of nowhere. It's hard feel inner peace when you hurt your back just by sneezing too hard.

But I also remind myself that my wife and I walk two miles every day. I had a cardiac stress test not too long ago that the doctor described as "excellent for my age and gender." We're going to the Grand Canyon later this year, something we had planned to do almost 30 years ago. My FL is stable, and my  dermatologist didn't find any new skin cancer the last time I saw her. There's lots to be thankful for.  Lots of reasons to feel some peace.

I try to find peace in the small things. I can always find peace there.

I hope you can find some peace today, too. Maybe looking at the whole world might not do it. Maybe looking at your small part of the world might not do it, either.  

Look for the small, quiet places were peace tends to stay. Go there for a little while. Enjoy it.

I wish you a Merry Christmas, and many, many peaceful moments to come.

 

 

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.