Tumor Microenvironment in POD24

Well, the winners of the Social Health Awards were announced yesterday, and unfortunately I did not win either of the awards that I was a finalist for. That's fine -- it really was an honor to make it to the finals, and the winners of all 10 awards do really amazing work. So I'm happy for them. And I thank you all again for all of your support, during the awards nominations and over the last 14+ years. 

I'll keep doing what I do.

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Very cool research from the Journal of Hematology and Oncology, getting us one step closer (we hope) to figuring out the mystery of POD24.

A little background first. POD24 (sometimes called EFS24) stands for Progression of Disease within 24 Months. It's the idea that, for Follicular Lymphoma patients who have recieved successful immunochemotherpay (like R-CHOP or B +R), if the disease returns within 24 months, their outcomes are worse than other FL patients. Some research published earlier this year suggests that the media 5 year survival for FL patients is about 90%, but for POD24 patients, it's about 50%.

Figuring out POD24 is a big priority in the Lymphoma community. There are so many unanswered questions about FL in general, and even more for POD24. There have been lots of attempts to find biomarkers for POD24 -- something in the cells or the genes -- that can help doctors identify POD24 patients early on and treat the disease aggressively.  Or, even better, create new treatments that will act on those biomarkers in some way.

The research published in JHO is the latest attempt at finding biomarkers. The article is called "Revealing the evolution of the tumor immune microenvironment in follicular lymphoma patients progressing within 24 months using single-cell imaging mass cytometry." It involves some pretty heavy science, but I think it's fascinating.

A lot of cancer research lately focuses on the "tumor microenvironment." Basically, this is research that works on the assumption that cancer cells don't just survive because of what is in the cell themselves. Instead, they rely on things happening on their micro-environment -- the area that is right around the cell. There must be something nearby that is protecting the cell in some way.

This research looks at the ways that the body's immune system protects FL cells. The body does produce abnormal cells from time to time, and typically, the immune system recognizes them as problematic, and takes care of them before they can become an issue. But sometimes, something happens that allows them to slip past the immune system and become a problem. That's what might happen with POD24, according to this research -- the immune stystem not only allows the FL cells to keep growing, but might play an active role in protecting the cells.

Our immune system is kind of amazing. It has lots of different layers, so certain cells kind of float around and take care of simple problems. If they can't handle a problem, a different set of immune cells comes in to help, and sends out signals to even more immune cells. And if they can't handle it, even more powerful immune cells come in to help. 

(Of course, there are downsides to all of this. Our body reacts to all of this immune activity in ways that can be problematic, too. Cytokine Release Syndrome, for example, is a potentially serious side effect of CAR-T therapy that happens when the immune system is over-activated.)

 As for the research in the article, the researchers found that the tumor microenvironment -- the area that surrounds the cancer cells -- created a barrier to the FL cells, so immune cells could not get to them. They did this by recruiting certain immune cells (regulatory T cells) and macrophages (very powerful immune cells). It is especially important that the cancer cells can control the regulatory T cells, since these are the immune cells that control (or regulate) how the body is going to respond to an immune problem. 

The researchers looked especially at proteins that were on the immune cells that were causing the problems, and identified which cells had certain proteins or were missing certain proteins. (If you're interested in the specifics, the article says:

"More FL-cells in the peri-follicular regions suffered CD8⁺T cells attacks under simultaneous protection of regulatory T cells (Tregs) and/or macrophages compared with that in the follicles irrespective of POD24. During POD24, increased CD163⁻ macrophages with PD-1 ligand upregulation and decreased CD8⁺T cells with upregulated LAG-3 expression around FL-cells were observed in the follicles.")

The details matter to researchers, because those are the potential targets for any new treatments. Immunotherapy is all about using the body's immune system to treat cancer, either by changing the immune cells to recognize cancer cells, or by changing cancer cells so the immune system can control them. The researchers in the article hope that identifying those specific cells, and the specific features on those cells, can eventually lead to treatments that can target them.   

And that's the other really important thing to remember about this research: it's still just taking place in a laboratory, looking at cells and not at whole, complete people. This is very early research. In fact, it is published as a letter to the editor, rather than a peer-reviewed article. In other words, the research hasn't been reviewed by other researchers yet to validate it.

So while it's valuable, it will be a long time before it leads to any new treatments.

Still, I think it's pretty fascinating research, and it tells us something about how researchers are thinking about Follicular Lymphoma, and especially about how to handle the POD24 problem. It really is a priority for researchers, and even though it only affects about 20% of FL patients, it's nice to hear that those who are having the most difficulty are getting the attention.

And any new knowledge about FL and what makes it incurable is bound to help all of us. 

Secondary Cancers in Follicular Lymphoma

On my last post, a reader asked if I could write about other malignancies in Follicular Lymphoma treatments. My guess is that the request came because, in discussing the updated results of a trial in my last post, I mentioned the rates of secondary malignancies in the patients in the study -- that is, how many patients developed new cancers besides FL.

I'm not surprised at the request. As I was writing that, I kind of made a mental note to look into that statistic a little more, but the original full article didn't get into a whole lot of detail. But I also know that writing a statistic like that without any context is a nice way to get some people worried. My apologies for that -- I know how worrisome statistics can be, and as I've said in the past, the times that my disease has worried me most have been because I've read some statistic and it got stuck in my head.

So I want to add some more context to that statement, and give a little more information from the past couple of years about secondary malignancies in FL.

But first, I'll remind everyone of something important -- I am not a medical doctor, or a cancer researcher, or a biologist. I'm just a cancer patient who reads a lot. If you have concerns about your disease, the best person to talk to is your doctor.

Now on to the recent research.

I actually wrote about this topic a few months ago, describing research done this year on secondary cancers in Non Hodgkin's Lymphomas, including FL. The research describes a study of patients with NHL in Sweden, looking at a large database of 30,000 patients that tracked how many of them developed a second cancer after treatment. The study compared the 30,000 NHL patients with another database of 30,000 who did not have NHL, and compared how many of them developed cancer over time. Doing this allowed the researchers to see how much more likely a lymphoma patient was to develop cancer than the general population. If a study just said "FL patients have a 12% chance of developing a secondary cancer," that might seem bad. But if the same study says everyone in the world has a 10% chance of developing cancer, then to me, that 12% doesn't seem quite so bad. 

You can read the original article in the link above, and read my (non-expert) commentary, but the conclusion comes down to a few things.

First, Lymphoma patients do have a higher risk of developing secondary cancers than the general population, according to this study. However, that risk also stayed steady over the years in the study (1993 to 2014), and actually decreased for some cancers or Follicular Lymphoma patients. The decrease seemed to come from more patients receiving treatments other than traditional chemotherapy (like CHOP or Bendamustine), which generally cause fewer secondary cancers. Let me explain that again: in the early years of this study, before Rituxan and other non-chemo treatments, FL patients were more likely to develop secondary cancers because they were more likely to receive chemo. As more non-chemo treatments become available (Ritixan and other monoclonal antibodies, R-Squared, Inhibitors, CAR-T and other immunotherapies), the chances of developing a secondary cancer become smaller.

Let's look at another study, this one from 2021 that looked at over 13,000 FL patients from the Netherlands. It's called "Risk of second primary malignancies in patients with follicular lymphoma: a population-based study in the Netherlands, 1989-2018." It's very similar to the study of FL patients in Sweden, and comes up with some very similar results.

The Swedish study found that 11% of FL patients eventually developed a secondary cancer, while the study from the Netherlands found that about 12% developed one. Patients were more likely to develop a secondary cancer the farther out from their diagnosis that they went. This makes sense -- in the general population, older people are more likely to develop cancer than younger people. 

The cancer most likely to be found? Squamous Cell Carcinoma of the skin. (Interestingly, William also commented on the last post, pointing out that his wife, an FL patient, has had several basal and squamous skin lesions removed. Thank you, William -- you're always on top of things, even before I ask.)

Other secondary cancers include myeloproliferative neoplasms (MPNs), and myelodysplastic syndromes (MDS), which can lead to leukemias (although the article from Sweden had good news about this for FL patients), and solid tumor cancers of the mouth, stomach, colon and rectum, and  kidney.

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So what to make of all of this?

I think it's fair to say that secondary cancers are just unavoidable for a segment of the FL population -- a little over 10% of us. As the study from the Netherlands points out, our higher risk of secondary cancer comes from treatments like chemotherapy that can damage DNA and cause irregular cells to develop. But the fact that we have a cancer that affects our immune system is also an issue, according to those same researchers. Our bodies don't have as strong a response to factors that might cause cancer as others might have.

So what can we do about it?

Well, for me, I've always tried to be vigilant about how I feel. I see a dermatologist every year, who checks me for possible skin cancers. If skin cancers are the most common secondary cancer for FL patients, that seems like an easy one. I also get whatever regular screenings I'm supposed to get (just had a colonoscopy a few months ago, and I have an annual physical every year). I like to think that I am in tune with my body, and I know when something doesn't seem right. I don't take chances with my health, and if something is bothering me and a doctor dismisses it, I don't take No for an answer when I want it followed up. Self-awareness and self-advocacy won't stop cancers from happening, but they may help them get caught early, when they're more treatable.

As far as self-advocacy goes, I think it's very important to talk to your doctor about treatment options when the time comes for treatment. Bring up concerns about short-term side effects, but ask questions about long-term side effects too. If you have heart issues or a family history of hearty issues, that's worth mentioning. And if you have concerns about developing a secondary cancer, that should be discussed as well. Hopefully, your oncologist can give you information to ease your fears, or suggest another treatment that might be as effective. If not, try to get a second opinion from someone who does that for you. But also understand that sometimes the best treatment might be one that increases the chances of a secondary cancer. 

I also like this advice about secondary cancers from MD Anderson Cancer Center. To me, it puts things in perspective. Secondary cancers can develop for reasons that have nothing to do with cancer treatments -- some cancers are hereditary, for example. I try my best to not obsess about the decisions I have made.

I'd like to be able to end on a positive note, which is hard, but I'll go back to what I said about self-awareness and self-advocacy. Secondary cancers are not inevitable, but they do happen. Before treatment, ask questions about possible long-term side effects. Use that knowledge to be aware of your own body and possible changes to it, and be sure that any concerns you have are not dismissed. When a patient has a recurrence of FL, research shows that most of the time, the recurrence is found by the patient. Not by the doctor, or by a scan, or by a blood test. But because something didn't feel right to the patient.

So trust yourself and your ability to know your body.

And in the meantime, enjoy your life as best you can.

R-Squared Is Still Great

The Journal of Clinical Oncology has an update on the RELEVANCE trial. The very short summary is:  R-Squared is still great for Follicular Lymphoma.

Just as a reminder -- R-Squared is the name given to the combination of Rituxan and Lenalidomide (also known as Revlimid). The combination has already been approved by the FDA for FL patients who had already received another treatment. In short, the trials that led to the approval found that R-Squared was as effective as Rituxan + chemotherapy + Rituxan Maintenance. It was also considered more or less as safe as the chemo routine -- there were different side effects with R-Squared than with chemo, but not necessarily more dangerous side effects.

The approval was a big deal -- it showed that a non-chemotherapy treatment could be as effective as a chemotherapy. To me, that was a big deal in a sort of emotional sense, too. Many patients fear the word "chemotherapy" because they have probably seen its negative effects on family and friends. So to be able to tell a patient "this is NOT chemo" might make the emotional and psychological burden of cancer treatment just a tiny bit easier, at least for some people.

The article is called "Six-Year Results From RELEVANCE: Lenalidomide Plus Rituximab (R²) Versus Rituximab-Chemotherapy Followed by Rituximab Maintenance in Untreated Advanced Follicular Lymphoma," and it is an update on the trial that compared R-Squared to Chemotherapy in patients who had not yet been treated.

As the title suggests, this article reports on a six year follow-up of the 1030 patients in the trial (a pretty big number of patients). One important element of a treatment is durability -- sometimes a new treatment will take care of the cancer immediately, but then the cancer can come back in a matter of months. A six-year follow-up is a pretty good indicator of durability.

The results of the study showed that R-Squared remained just as effective after 6 years as it had been up to that point. The Progression-Free Survival (showing that the disease didn't get worse after 6 years) was 60% for R-Squared and 59% for R-chemo. Overall Survival was 89% for both groups. The transformation rate (the slow-growing FL turned into a fast-growing cancer) per year was 0.68% for R-Sqaured and 0.45% for R-chemo, and secondary primary malignancies (patients developed a new, different cancer) was 11% for R-Squared and 13% for R-chemo. There are some other statistical comparisons as well, but they all say the same thing -- R-Squared is as effective as R-chemo, and as safe.

The conclusion is pretty straightforward: R-Squared is a safe, effective alternative to chemotherapy for FL patients who have not yet been treated. 

This article is an update of a presentation made at ASH last December. Because it has been published, it is now considered peer-reviewed. That means the data has been checked by other experts. 

It's great news for us -- or for those of you who have not yet received treatment, anyway. R-Squared is not yet approved by the FDA as a first treatment for FL (it has only been approved for patients who have already had two other treatments). It will be interesting to see if this update leads to an FDA application for approval (though they don't seem to be in a big hurry). If so, that's one more option for FL patients.  

And that's good news.

Vitamin D and Magical Thinking

I saw an article this morning on Vitamin D and Large B Cell Lymphoma, and I had to share and comment. Not necessarily about the research itself -- it doesn't have much of anything to do with anyone reading this blog -- but because of the reminders it gave me about a bunch of issues related to my experience as a cancer patient.

The article is called "Vitamin D Insufficiency and Clinical Outcomes with Chimeric Antigen Receptor T-Cell Therapy in Large B-cell Lymphoma: Vitamin D insufficiency and CAR-T in LBCL," and will appear in the journal Transplantation and Cellular Therapy. I won't get too much into the details, but here's the study:

(To be clear here -- this is NOT a study involving Follicular Lymphoma patients.)

The researchers (there are a lot of them) wanted to know if blood levels of Vitamin D had an effect on CAR-T in LBCL patients. This is an observational study, not a clinical trial. In other words, they looked at a bunch of patients in one cancer center, rather than developing strict criteria for who could be a part of a study. They ultimately looked at 111 patients with relapsed or refractory LBCL who were about to be treated with CAR-T. They divided the patients into two groups -- one for patients with low vitamin D levels, and the other for patients with normal levels.

They found that, after 100 days, the Response Rate was 55% for the low Vitamin D patients, and 76% for the normal Vitamin D patients. After 2 years, the survival was 41% (low) and 71% (normal). They also found that the T cells that were taken from patients and then changed and put back into the patients were more viable for the patients who had normal Vitamin D levels. In other words, the cells lasted longer and worked better when Vitamin D levels were normal.

The authors were very clear that this was a very narrow study, looking at patients in one cancer center, and the idea that Vitamin D might help LBCL patients getting CAR-T needs to be studied more. Interesting study, but we can't get too excited about it.

That said, I'm excited about it. And that's kind of a problem.

I've been interested in Vitamin D and its relationship to cancer for a long time. There really isn't any definitive research that says Vitamin D will help cancer patients -- and certainly no research that says it will cure cancer. But it seems like there are enough small, focused research studies that, if you put them all together, like pieces of a puzzle, they suggest that there is a connection between the two.

And here's why it's a problem that I think that way.

It's bad science. And I value science and what it tells us about cancer treatments. But a whole bunch of studies that say "maybe, kind of" isn't the same as one study that says "Yes!"

All of this just reminds me of what makes it hard to be a cancer patient. It's a constant battle between the head and the heart. Science tells our heads that something is or isn't true, and our rational sides can understand that. But then there's the heart -- the emotional side -- that wants something easy and safe to be true. There's always a little bit of magical thinking in all of us. A teaspoon of turmeric, or a broccoli sprout sandwich, or 20 minutes on a trampoline every day will keep the cancer away. If only it was that easy. But I'm pretty sure it's not. 

And that's my complicated history with Vitamin D. I've been taking it for years. I've read enough about how Vitamin D might help a whole bunch of health issues that I'm too invested to think it won't help. This is called a "sunk cost fallacy." People refuse to change their minds about something because they've spent so much time and effort believing in it that they don't want to give up on it.

And since I've been taking Vitamin D for about as long as I have gone without treatment, it's easy to connect the two. (That's another fallacy -- correlation doesn't equal causation. I also had a big change happen at work at the same time. By that logic, I could say the change in my job is what caused my cancer to go away. I can guarantee that wasn't the case.)

So for me, the big lesson here is not to tell you to give up on magical thinking, and only do things that are backed up by science. That would be a little hypocritical. 

The lesson is that we need to choose which things we think magically about. I have real problems with patients who decide not to go with conventional treatment like chemotherapy or immunotherapy, and instead think that massive doses of vitamin D or bowls of broccoli will cure them. That strikes me as foolish, when there is science to back up that it could be effective in keeping you alive.

But going through chemo, and then switching to a vegetarian diet, or taking fish oil and Vitamin D, or exercising 60 minutes a day? Sure. None of those "extra" things will harm you, and most will help you stay healthier, even if they don't have any effect on your cancer. 

And maybe more importantly, apart from the long-term benefits that they might have, sometimes we just need something magical to get us through the day. Maybe it's a broccoli sprout sandwich. Maybe it's calling yourself a "cancer warrior." Maybe it's saying a prayer to St. Peregrine. There's no way that science will tell you it works. But maybe it helps us be at peace, even for a little while.

So I'm going to keep taking my Vitamin D. Please don't ask me what my levels are, or how much I take each day. I'm not here to give you medical advice. Ask your doctor if that's something that might help you.

But also trust that some things are OK, even if your doctor, or some other rational person who hasn't lived your experience, tells you otherwise. 

Immunotherapies Podcast

I'm having some issues with pain in my hand and wrist lately, so I'm not going to write much today. (At least I'll try not to. I usually tell myself that, and then get carried away. Haters gonna hate, and writers gonna write, as the kids say.)

So I'm going to share a link to the Leukemia and Lymphoma Society's podcast, called The Bloodline with LLS. Their most recent episode is called "Immune System To The Rescue: Immunotherapies In Blood Cancer." It features an interview with Dr. John Leonard of Weill Cornell Medicine in New York.

 I've written about and linked to Dr. Leonard a bunch of times in the past, especially just before the ASH conference every December, when he publishes the Leonard List -- his top 10 most exciting presentations at ASH. I like him a lot -- a great researcher, and someone who knows how to explain complex subjects to non-experts.

Dr. Leonard's topic is Immunotherapy for blood cancers (not just for Follicular Lymphoma). Immunotherapy is a large group of treatments, not one single treatment. I see it discussed a lot as a fourth approach to cancer treatment -- we've had chemotherapy, radiation, and surgery for a long time, and now we have Immunotherapy.

What makes Immunotherapy different from other cancer treatments is that it involves the patient's immune system in some way. As you probably know, our immune systems fight off outside invaders that might do harm to our bodies -- things like viruses and bacteria. One of the reasons our immune systems can't fight off cancer cells is that they don't come from the outside, like a virus. Cancer cells are our own cells. Our immune systems don't usually attack our own bodies (and when they do, you have an autoimmune disease, which causes its on set of problems). 

So Immunotherapies usually take one of two approaches, which allow the immune system to go after cancer cells. First, the treatment can change the immune system so it treats cancer cells as something bad. This is how CAR-T works -- T cells are removed from the body, changed in a lab, and then put back into the body. The second approach is to change the cancer cell, so the immune system can take care of it. This is how checkpoint inhibitors work -- they change the cancer cell so the immune system can recognize it as a problem.

Dr. Leonard goes into more detail about all of this, discusses some of the more common immunotherapies (like Rituxan, which has been around for 25 years now), and some of the newer and more exciting ones (like CAR-T and bi-specifics). 

It's a really interesting discussion, and a nice introduction to Immunotherapy. As I said, Dr. Leonard is very good at explaining difficult concepts in fairly easy language. You can listen to the podcast here (it's about 45 minutes long). If you'd rather read the transcript, or you need it for translation, you can find a pdf of it here.

And now, I'm off the rest my hand. 

More to come soon.

Social Health Awards: Finalist!

Great news to share -- I have been named a finalist for two Social Health Awards for this year!

Of course, I have all of you to thank. I really appreciate your endorsements, and all of the inspiration you give me. You don't know how much I enjoy your comments, and your emails, letting me know that you appreciate the blog, and letting me share your lives just a little bit.

I received the email announcement this afternoon. I am one of six finalists for the Creative Contributor award and for the Revolutionary Researcher award. Winners will be announced in a few weeks. You can read more about the awards, and see links to the other nominees for all of awards here. 

It's an impressive bunch of advocates, I have to say. I've met a few of them in the past, so I know how passionate they are about helping their communities. I'm so pleased and honored to be among them. 

I'm especially proud to be a finalist for the Revolutionary Researcher award. I've told my story plenty of times on the blog. As I've said before, I'd probably keep doing the research on Follicular Lymphoma and writing the blog even if I was the only one who ever read it. It gives me an excuse to stay up-to-date on what is happening in the Follicular Lymphoma community. I need to know what's there for me next. I need that to stay hopeful. It's kept me grounded for amost 15 years.

And it makes me happy knowing I can do the same for all of you, too.

So thanks again. 

Back to work now. I'll share more research soon.